Publications by authors named "John L Neumeyer"

54 Publications

The High Affinity Dopamine D Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders.

ACS Chem Neurosci 2021 04 12;12(8):1428-1437. Epub 2021 Apr 12.

Division of Basic Neuroscience, Medicinal Chemistry Laboratory, McLean Hospital, Belmont, Massachusetts 02478, United States.

The dopamine D receptor exists in two different states, D and D; the former is the functional form of the D receptor and associates with intracellular G-proteins. The D agonist [H]MCL-536 has high affinity for the D receptor ( 0.8 nM) and potently displaces the binding of (-(-)---propylnorapomorphine (NPA; 0.16 nM) and raclopride ( 0.9 nM) in competition binding assays. Here, we further characterize [H]MCL-536. [H]MCL-536 was metabolically stable, with about 75% of the compound remaining intact after 1 h incubation with human liver microsomes. Blood-brain barrier penetration in rats was good, attaining at 15 min a % injected dose per gram of wet tissue (%ID/g) of 0.28 in males versus 0.42 in females in the striatum. Specific uptake ratios ([%ID/g striatum]/[%ID/g cerebellum]) were stable in males during the first 60 min and in females up to 15-30 min. The D-rich striatum exhibited the highest uptake and slowest washout compared to D-poor cortex or cerebellum. In peripheral organs, uptake peaked at 15 min but declined to baseline at 60 min, indicating good clearance from the body. autoradiography on transaxial and coronal brain sections showed specific binding of [H]MCL-536, which was abolished by preincubation with D/D ligands sulpiride, NPA, and raclopride and in the presence of the stable GTP analogue guanylylimidodiphosphate. In amphetamine-sensitized animals, striatal binding was higher than in controls, indicating specificity for the D receptor state. [H]MCL-536's unique properties make it a valuable tool for research on neurological disorders involving the dopaminergic system like Parkinson's disease or schizophrenia.
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http://dx.doi.org/10.1021/acschemneuro.1c00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426090PMC
April 2021

Identification of fluorinated (R)-(-)-aporphine derivatives as potent and selective ligands at serotonin 5-HT receptor.

Bioorg Med Chem Lett 2019 01 23;29(2):230-233. Epub 2018 Nov 23.

Division of Basic Neuroscience, Medicinal Chemistry Program, McLean Hospital, Belmont, MA 02478, United States; Department of Psychiatry, Harvard Medical School, Boston, MA 02115, United States.

A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT hit ligands with high selectivity over other 5-HT receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.
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http://dx.doi.org/10.1016/j.bmcl.2018.11.050DOI Listing
January 2019

New Dopamine D2 Receptor Agonist, [H]MCL-536, for Detecting Dopamine D2high Receptors in Vivo.

ACS Chem Neurosci 2018 06 16;9(6):1283-1289. Epub 2018 Apr 16.

Division of Basic Neuroscience, Medicinal Chemistry Laboratory , McLean Hospital , Belmont , Massachusetts 02478 , United States.

Increases in the D2 receptor high affinity state are associated with certain neurological disorders. We synthesized and characterized the high-affinity D2high ligand [H]MCL-536 in competition binding against the D2/3 agonist R-(-)- N- n-propylnorapomorphine (NPA) and the D2/3 antagonist raclopride. The total binding of [H]MCL-536 (minus that in the presence of 100 nM NPA) was measured by saturation binding in CHO cells expressing human D2long; the data yielded separable, nonsaturable nonspecific, and saturable specific components. The former represents an aporphine site common to NPA and [H]MCL-536. The latter indicated specific binding to the total D2 receptors (both high and low-affinity states). [H]MCL-536 had a K of 0.8 nM. In competition binding, NPA had a K of 0.16 nM, and raclopride had a K of 0.9 nM. Co-incubation with guanylylimidodiphosphate abolished binding to D2high. This unique profile makes radiolabeled MCL-536 a versatile tool for diagnostics and therapeutics, and may quantify D2high sites in schizophrenia and PD patients in vivo.
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http://dx.doi.org/10.1021/acschemneuro.8b00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412031PMC
June 2018

Convenient synthesis of 18F-radiolabeled R-(-)-N-n-propyl-2-(3-fluoropropanoxy-11-hydroxynoraporphine.

J Labelled Comp Radiopharm 2014 Dec 17;57(14):725-9. Epub 2014 Nov 17.

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478-9106, USA.

Aporphines are attractive candidates for imaging D2 receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D2 antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D2 dysregulation, such as schizophrenia and Parkinson's disease. Accordingly, MCL-536 (R-(-)-N-n-propyl-2-(3-[(18)F]fluoropropanoxy-11-hydroxynoraporphine) was selected for labeling with (18)F based on in vitro data obtained for the non-radioactive ((19)F) compound. Fluorine-18-labeled MCL-536 was synthesized in 70% radiochemical yield, >99% radiochemical purity, and specific activity of 167 GBq/µmol (4.5 Ci/µmol) using p-toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination.
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http://dx.doi.org/10.1002/jlcr.3246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275395PMC
December 2014

Pharmacological characterization and therapeutic potential for the treatment of opioid abuse with ATPM-ET, an N-ethyl substituted aminothiazolomorphinan with κ agonist and μ agonist/antagonist activity.

Eur J Pharmacol 2014 Oct 3;740:455-63. Epub 2014 Jul 3.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address:

We previously reported that the κ agonists with mixed μ activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a κ agonist and μ agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel κ agonist and μ agonist/antagonist may have utility for the treatment of drug dependence.
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http://dx.doi.org/10.1016/j.ejphar.2014.06.045DOI Listing
October 2014

(18)F-MCL-524, an (18)F-Labeled Dopamine D2 and D3 Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study.

J Nucl Med 2014 Jul 1;55(7):1164-70. Epub 2014 May 1.

Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.

Unlabelled: PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D2 and D3 receptor (D2/D3) antagonists such as (11)C-raclopride. However, more recently developed agonist radioligands have shown enhanced sensitivity to endogenous dopamine. A limitation of available agonist radioligands is that they incorporate the short-lived radioisotope (11)C. In the current study, we developed the (18)F-labeled D2/D3 receptor agonist (R)-(-)-2-(18)F-fluoroethoxy-N-n-propylnorapomorphine ((18)F-MCL-524).

Methods: In total, 10 PET measurements were conducted on 5 cynomolgus monkeys. Initially, the binding of (18)F-MCL-524 was compared with that of (11)C-MNPA in 3 monkeys. Second, the specificity of (18)F-MCL-524 binding was examined in pretreatment studies using raclopride (1.0 mg/kg) and d-amphetamine (1.0 mg/kg). Third, a preliminary kinetic analysis was performed using the radiometabolite-corrected arterial input function of the baseline studies. Finally, 2 whole-body PET measurements were conducted to evaluate biodistribution and radiation dosimetry after intravenous injection of (18)F-MCL-524.

Results: (18)F-MCL-524 entered the brain and provided striatum-to-cerebellum ratios suitable for reliable quantification of receptor binding using the multilinear reference tissue model. Mean striatal nondisplaceable binding potential (BPND) values were 2.0 after injection of (18)F-MCL-524 and 1.4 after (11)C-MNPA. The ratio of the BPND values of (18)F-MCL-524 and (11)C-MNPA was 1.5 across striatal subregions. After administration of raclopride and d-amphetamine, the (18)F-MCL-524 BPND values were reduced by 89% and 56%, respectively. Preliminary kinetic analysis demonstrated that BPND values obtained with the 1-tissue- and 2-tissue-compartment models were similar to values obtained with the multilinear reference tissue model. Estimated radiation doses were highest for gallbladder (0.27 mSv/MBq), upper large intestine (0.19 mSv/MBq), and small intestine (0.17 mSv/MBq). The estimated effective dose was 0.035 mSv/MBq.

Conclusion: The (18)F-labeled agonist (18)F-MCL-524 appears suitable for quantification of D2/D3 receptor binding in vivo, and the results encourage extension to human studies. The longer half-life of (18)F makes (18)F-MCL-524 attractive for studies on modulation of the dopamine concentration-for example, in combination with simultaneous measurement of changes in blood-oxygen-level-dependent signal using bimodal PET/functional MRI.
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http://dx.doi.org/10.2967/jnumed.113.133876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587887PMC
July 2014

Preliminary pharmacological evaluation of enantiomeric morphinans.

ACS Chem Neurosci 2014 Feb 8;5(2):93-9. Epub 2014 Jan 8.

Alcohol & Drug Abuse Research Center, ‡Mailman Research Center, McLean Hospital, Harvard Medical School , 115 Mill Street, Belmont, Massachusetts 02478, United States.

A series of levo- and dextromorphinan pairs have been synthesized and evaluated for their affinities to the mu, kappa, and delta opioid receptors, the N-methyl-D-aspartate (NMDA) channel, and sigma 1 and 2 receptors. It was found that levo isomers tended to have higher affinities at the opioid receptors and moderate to high affinities to the NMDA and sigma receptors, while dextro isomers tended to have lower affinities to the opioid receptors but comparatively higher affinities to the NMDA and sigma receptors. This series of compounds have interesting and complex pharmacological profiles, and merit further investigation as potential therapies for drug abuse treatment.
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http://dx.doi.org/10.1021/cn400205zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930996PMC
February 2014

Synthesis and pharmacological evaluation of aminothiazolomorphinans at the mu and kappa opioid receptors.

J Med Chem 2013 Nov 29;56(21):8872-8. Epub 2013 Oct 29.

Alcohol & Drug Abuse Research Center, ‡Mailman Research Center, McLean Hospital, Harvard Medical School , 115 Mill Street, Belmont, Massachusetts 02478, United States.

Previous studies with aminothiazolomorphinans suggested that this class of opioid ligands may be useful as a potential pharmacotherapeutic to decrease drug abuse. Novel aminothiazole derivatives of cyclorphan were prepared to evaluate a series of aminothiazolomorphinans with varying pharmacological properties at the κ opioid receptor (KOR) and μ opioid receptor (MOR). This study was focused on exploring the regioisomeric analogs with the aminothiazole on the C-ring of the morphinan skeleton. Receptor binding and [(35)S]GTPγS binding assays were used to characterize the affinity and pharmacological properties of the aminothiazolomorphinans. Intracranial self-stimulation (ICSS) was used to compare the effects of a representative aminothiazolomorphinan with the morphinan mixed-KOR/MOR agonist butorphan (MCL-101) on brain-stimulation reward.
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http://dx.doi.org/10.1021/jm401290yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880591PMC
November 2013

Update 1 of: Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders.

Chem Rev 2013 May 7;113(5):PR123-78. Epub 2013 Mar 7.

CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China 201203.

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http://dx.doi.org/10.1021/cr300113aDOI Listing
May 2013

Synthesis, binding affinity, and functional in vitro activity of 3-benzylaminomorphinan and 3-benzylaminomorphine ligands at opioid receptors.

J Med Chem 2012 Apr 4;55(8):3878-90. Epub 2012 Apr 4.

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.

A series of 3-benzylamino-3-desoxymorphinan (I) and 3-benzylamino-3-desoxymorphine (II) derivatives were synthesized and evaluated for their binding affinities, and functional activity data are presented at MOR, KOR, and DOR. Some of these ligands were found to have high binding affinity at MOR and KOR and displayed increased selectivity at MOR over KOR and DOR compared to butorphan or cyclorphan. The most selective compound, 3-(3'-hydroxybenzyl)amino-17-methylmorphinan (4g) (24-fold MOR to KOR and 1700-fold MOR to DOR) also showed high binding affinity (0.42 nM to MOR) and was a full agonist in the [(35)S]GTPγS binding assay. 2-(3'-Hydroxybenzyl)amino-17-cyclopropylmethylmorphinan (17) was found to be a KOR-selective ligand (150-fold over MOR and >10000-fold over the DORs). Most 3-benzylaminomorphinan derivatives were partial agonists at MOR and full agonists at KOR in the [(35)S]GTPγS binding assay.
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http://dx.doi.org/10.1021/jm3001086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375359PMC
April 2012

A tribute to Joseph G. Cannon, 1926-2011.

Authors:
John L Neumeyer

J Med Chem 2012 Feb 6;55(4):1423. Epub 2012 Feb 6.

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http://dx.doi.org/10.1021/jm300081mDOI Listing
February 2012

Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors

ACS Med Chem Lett 2011 Mar;2(3):189-194

Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478-9106 USA.

The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.
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http://dx.doi.org/10.1021/ml1001689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110009PMC
March 2011

Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for κ, μ, and δ opioid receptors.

Bioorg Med Chem 2011 May 26;19(9):2808-16. Epub 2011 Mar 26.

Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478-9106, USA.

A novel series of homo- and heterodimeric ligands containing κ/μ agonist and μ agonist/antagonist pharmacophores joined by a 10-carbon ester linker chain were synthesized and evaluated for their in vitro binding affinity at κ, μ, and δ opioid receptors, and their functional activities were determined at κ and μ receptors in [(35)S]GTPγS functional assays. Most of these compounds had high binding affinity at μ and κ receptors (K(i) values less than 1nM). Compound 15b, which contains butorphan (1) at one end of linking chain and butorphanol (5) at the other end, was the most potent ligand in this series with binding affinity K(i) values of 0.089nM at the μ receptor and 0.073nM at the κ receptor. All of the morphinan-derived ligands were found to be partial κ and μ agonists; ATPM-derived ligands 12 and 11 were found to be full κ agonists and partial μ agonists.
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http://dx.doi.org/10.1016/j.bmc.2011.03.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095849PMC
May 2011

Aminothiazolomorphinans with mixed κ and μ opioid activity.

J Med Chem 2011 Mar 25;54(6):1903-13. Epub 2011 Feb 25.

Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478, United States.

A series of N-substituted and N'-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower than their prototype aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [(35)S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N'-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse medications.
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http://dx.doi.org/10.1021/jm101542cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068608PMC
March 2011

Opioid bifunctional ligands from morphine and the opioid pharmacophore Dmt-Tic.

Eur J Med Chem 2011 Feb 8;46(2):799-803. Epub 2010 Dec 8.

Department of Toxicology, University of Cagliari, Via Ospedale 72, I-09124 Cagliari, Italy.

Bifunctional ligands containing an ester linkage between morphine and the δ-selective pharmacophore Dmt-Tic were synthesized, and their binding affinity and functional bioactivity at the μ, δ and κ opioid receptors determined. Bifunctional ligands containing or not a spacer of β-alanine between the two pharmacophores lose the μ agonism deriving from morphine becoming partial μ agonists 4 or μ antagonists 5. Partial κ agonism is evidenced only for compound 4. Finally, both compounds showed potent δ antagonism.
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http://dx.doi.org/10.1016/j.ejmech.2010.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035428PMC
February 2011

Effects of ATPM-ET, a novel κ agonist with partial μ activity, on physical dependence and behavior sensitization in mice.

Acta Pharmacol Sin 2010 Dec 22;31(12):1547-52. Epub 2010 Nov 22.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.

Aim: to investigate the effects of ATPM-ET [(-)-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice.

Methods: the pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice.

Results: the binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ- and μ-opioid receptors with K(i) values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED(50) value of 2.68 (2.34-3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization (P<0.05).

Conclusion: ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.
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http://dx.doi.org/10.1038/aps.2010.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002947PMC
December 2010

Rapid access to morphinones: removal of 4, 5-ether bridge with Pd-catalyzed triflate reduction.

Tetrahedron Lett 2010 Apr;51(17):2359-2361

Medicinal Chemistry Program, Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478.

A new synthetic method for the removal of the 4, 5-bridged ether moiety of several opioids has been developed. This process offers a faster, simpler synthetic route to obtain the morphinone scaffold in high yields without the need for protection of the ketone moiety.
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http://dx.doi.org/10.1016/j.tetlet.2010.02.146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872489PMC
April 2010

Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore.

ACS Chem Neurosci 2010 Feb;1(2):155-164

Department of Toxicology, University of Cagliari, I-09124, Cagliari, Italy.

Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.
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http://dx.doi.org/10.1021/cn900025jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843921PMC
February 2010

Effect of linker substitution on the binding of butorphan univalent and bivalent ligands to opioid receptors.

Bioorg Med Chem Lett 2010 Mar 25;20(5):1507-9. Epub 2010 Jan 25.

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.

A series of bivalent hydroxy ether butorphan ligands were prepared and their binding affinities at the opioid receptors determined. Addition of a hydroxy group to a hydrocarbon chain can potentiate binding affinity up to 27- and 86-fold at the mu and kappa opioid receptors, respectively. Two bivalent ligands with sub-nanomolar binding affinity at the mu and kappa opioid receptors were discovered.
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http://dx.doi.org/10.1016/j.bmcl.2010.01.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834170PMC
March 2010

Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: ligands for mu, kappa, and delta opioid receptors.

J Med Chem 2010 Jan;53(1):402-18

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.

The phenolic group of the potent mu and kappa opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with para-substituents in the benzene ring. These compounds are highly potent mu and kappa ligands, e.g., p-methoxyphenylaminocyclorphan showing a K(i) of 0.026 nM at the mu receptor and a K(i) of 0.03 nM at the kappa receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted 3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3-hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminomethyl groups, amide bonds, and hydroxymethylene groups, respectively. Although most of the 2-substituted morphinans showed considerably lower affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher affinities compared to the univalent 2-substituted morphinans.
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http://dx.doi.org/10.1021/jm9013482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814335PMC
January 2010

Univalent and bivalent ligands of butorphan: characteristics of the linking chain determine the affinity and potency of such opioid ligands.

J Med Chem 2009 Dec;52(23):7389-96

Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.

Bivalent morphinan compounds containing ester linkers were synthesized and their binding affinities at the mu, delta, and kappa opioid receptors determined. Addition of methyl groups adjacent to the hydrolytically labile ester linkage increased stability while only partially affecting binding affinity. The resulting bivalent ligands with optimized spacer length and structure show potent binding profiles with the most potent compound (4b), having K(i) values of 0.47 nM for both the mu and kappa opioid receptors, and 4a, having K(i) values of 0.95 and 0.62 nM for the mu and kappa receptors, respectively. Both 4a and 4b were partial agonists at the kappa and micro receptors in the [(35)S]GTPgammaS binding assay.
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http://dx.doi.org/10.1021/jm900379pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788666PMC
December 2009

Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects.

PLoS One 2009 Jun 5;4(6):e5811. Epub 2009 Jun 5.

State Key laboratory of Drug Research, Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

(+/-) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005811PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690691PMC
June 2009

Pharmacological characterization of ATPM [(-)-3-aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a novel mixed kappa-agonist and mu-agonist/-antagonist that attenuates morphine antinociceptive tolerance and heroin self-administration behavior.

J Pharmacol Exp Ther 2009 Apr 9;329(1):306-13. Epub 2009 Jan 9.

School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.

ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed kappa- and mu-opioid activity and identified to act as a full kappa-agonist and a partial mu-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by kappa- and mu-, but not delta-opioid, receptors. In addition to its agonist profile on the mu-receptor, ATPM also acted as a mu-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED(50) value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed kappa-agonist and mu-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. kappa-Agonists with some mu-activity appear to offer some advantages over selective kappa-agonists for the treatment of heroin abuse.
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http://dx.doi.org/10.1124/jpet.108.142802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670601PMC
April 2009

Synthesis and neuropharmacological evaluation of esters of R(-)-N-alkyl-11-hydroxy-2-methoxynoraporphines.

Bioorg Med Chem Lett 2009 Jan 13;19(1):51-3. Epub 2008 Nov 13.

Alcohol Drug Abuse Research Center and Mailman Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.

We synthesized several esters of R(-)-N-alkyl-11-hydroxy-2-methoxynoraporphines, assessed their affinities at dopamine D(1) and D(2) receptors in rat forebrain tissue and quantified their effects on motor activity in normal adult male rats. Tested compounds displayed moderate to high affinities to D(2) receptors but low affinities to D(1) receptors. The most D(2)-potent (K(i)=18.9nM) and selective novel agent (>529-fold vs D(1) sites) was R(-)-2-methoxy-11-acetyloxy-N-n-propylnoraporphine (compound 4b). At moderate doses, the compound proved to have prolonged behavioral locomotor activity.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.025DOI Listing
January 2009

Synthesis and pharmacological evaluation of hydrophobic esters and ethers of butorphanol at opioid receptors.

Bioorg Med Chem Lett 2008 Aug 17;18(16):4474-6. Epub 2008 Jul 17.

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.

We synthesized several hydrophobic esters and ethers of butorphanol and assessed their affinities at opioid receptors in CHO cell membranes. Tested compounds displayed moderate to high affinities to the mu and kappa receptors. The findings accord with previous evidence of a lipophilic binding pocket in the opioid receptors that can be accessed to afford good binding affinity without the need for a phenolic hydrogen-bond donor group. The most potent (K(i)=61 pM at mu and 48 pM at kappa) novel agent was (-)-N-cyclobutylmethylmorphinan-3-yl-14-ol phenoxyacetate (4d).
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http://dx.doi.org/10.1016/j.bmcl.2008.07.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745115PMC
August 2008

Synthesis and binding studies of 2-O- and 11-O-substituted N-alkylnoraporphines.

Bioorg Med Chem Lett 2008 Jul 10;18(14):3971-3. Epub 2008 Jun 10.

Alcohol Drug Abuse Research Center and Mailman Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.

We synthesized several novel 2-O- or 11-O-substituted N-alkylnoraporphines and assessed their affinities at dopamine D(1) and D(2), and serotonin 5-HT(1A) receptors in rat forebrain tissue. Tested compounds displayed moderate to high affinities to D(2) receptors but low affinities to D(1) and 5HT(1A) receptors. The findings accord with previous evidence of a lipophilic cavity on the surface of the D(2) receptor to accommodate N-alkyl moieties of aporphines. The most D(2)-potent (K(i)=97 nM) and selective novel agent (>100-fold vs. D(1) and 5-HT(1A) sites) was R(-)-2-(2-hydroxyethoxy)-11-hydroxy-N-n-propylnoraporphine (compound 11).
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http://dx.doi.org/10.1016/j.bmcl.2008.06.016DOI Listing
July 2008

In vivo characterization of (-)(-)MCL-144 and (+)(-)MCL-193: isomeric, bivalent ligands with mu/kappa agonist properties.

Neurochem Res 2008 Oct 5;33(10):2142-50. Epub 2008 Jun 5.

Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, P.O. Box 711, 601 Elmwood Ave., Rochester, NY, 14642-8711, USA.

Once opioid receptor dimers were postulated, a goal has been to synthesize and screen novel opioids, with the hope of furthering our knowledge of the structure-activity relationship of opioid ligands with the opioid receptors. The aim of the current study was to address whether two isomeric bivalent ligands would have pharmacological differences after central administration, in vivo. The two compounds, (-) bis(N-cyclobutylmethyl-morphinan-3-yl) sebacoylate dihydrochloride (MCL-144) and 1-((+)N-cyclobutylmethylmorphinan-3-yl)-10-((-) N-cyclobutylmethylmorphinan-3-yl)sebacolyate (MCL-193) are each linked by a 10-carbon chain ester. The active (-) enantiomer for both ligands is 3-hydroxy-N-cyclobutylmethyl morphinan ((-)MCL-101), a N-cyclobutylmethyl analogue of cyclorphan (J Med Chem 43:114-122, 2000). MCL-144 contains two active levo rotatory (-)(-) pharmacophores, while MCL-193 contains one active (-) and one inactive (+) pharmacophore of MCL-101. In vitro analysis demonstrated that all three compounds, (-)(-)MCL-144, (+)(-)MCL-193 and (-)MCL-101 were kappa agonists and mu partial agonists. (-)(-)MCL-144 and (-)MCL-101 had much higher affinity for both the mu and kappa opioid receptors compared to (+)(-)MCL-193. In vivo, (-)(-)MCL-144 and (+)(-)MCL-193 produced full dose-response curves, in the 55 degrees C tail-flick test, with each compound having an ED(50) value of 3.0 nmol after intracerebroventricular (i.c.v.) administration. The analgesic properties of both compounds were antagonized by the mu-selective antagonist, beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. Concomitant, i.c.v., administration of either (-)(-)MCL-144 or (+)(-)MCL-193 with morphine, did not significantly antagonize morphine-induced antinociception at any dose tested. In antinociceptive tests, (-)(-)MCL-144 and (+)(-)MCL-193 had the same pharmacological properties, demonstrating that having two active pharmacophores separated by a 10-carbon spacer group did not increase the antinociceptive efficacy of the compound. Additionally, it was also of interest to compare (-)(-)MCL-145 and (-)(-)MCL-144, as the only difference between these bivalent ligands is the spacer region connecting the two pharmacophores, yet (-)(-)MCL-145 produced an ED(50) value 10-fold lower than (-)(-)MCL-144 (ED(50) values = 0.3 nmol and 3.0 nmol, respectively).
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http://dx.doi.org/10.1007/s11064-008-9752-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574661PMC
October 2008

Synthesis and dopamine receptor affinities of N-alkyl-11-hydroxy-2-methoxynoraporphines: N-alkyl substituents determine D1 versus D2 receptor selectivity.

J Med Chem 2008 Feb 6;51(4):983-7. Epub 2008 Feb 6.

Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.

We developed a procedure to synthesize a series of N-alkyl-2-methoxy-11-hydroxynoraporphines from thebaine and evaluated their binding affinities at dopamine D1 and D2 receptors in rat forebrain tissue. At D2 receptors, the most potent 10,11-catechol-aporphine was (R)-(-)-2-methoxy-N-n-propylnorapomorphine (D2, Ki = 1.3 nM; D1, Ki = 6450 nM), and the most selective and potent 11-monohydroxy aporphine was (R)-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine (D2, Ki = 44 nM; D1, Ki = 1690 nM). In contrast, the N-methyl congeners (R)-(-)-2-methoxy-11-hydroxy-N-methyl-aporphine (D1 vs D2, Ki = 46 vs 235 nM) showed higher D1 than D2 affinity, indicating that N-alkyl substituents have major effects on D2 affinity and D2/D1 selectivity in such 2-methoxy-11-monohydroxy-substituted aporphines.
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http://dx.doi.org/10.1021/jm701045jDOI Listing
February 2008

Pharmacological characterization of the effects of dopamine D(1) agonists on eye blinking in rats.

Behav Pharmacol 2007 Dec;18(8):745-54

Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts 02478, USA.

Dopamine D(1)-like partial agonists antagonize some abuse-related effects of cocaine and have been proposed as candidate medications for psychostimulant abuse. Earlier studies have showed that D(1)-like agonists increase eye blinking in monkeys and that the magnitude of this effect may be related to agonist efficacy. These studies characterized the effects of D(1)-like agonists on eye blinking in female Sprague-Dawley rats placed in customized restraint tubes. After vehicle injections, eye blink rates averaged 2.1+/-0.25 blinks/min, or 31+/-4 blinks/15 min. The D(1)-like agonists SKF 82958 and R(+)-6Br-APB dose-dependently increased eye blinking to 136 and 124/15 min, respectively. The selective D(1)-like antagonist SCH 23390 decreased eye blinking and the peripherally selective D(1)-like agonist fenoldopam, the D(2)-like agonist (+)PHNO, and the indirect dopamine agonist methamphetamine all failed to alter eye blink rates relative to vehicle levels. Additional studies with unique congeners and isomers of the D(1)-like partial agonist SKF 83959, MCL 202, MCL 204, MCL 206, MCL 207 and MCL 209, resulted in only moderate increases in eye blink rates (27-84 blinks/15 min). These effects were dose-related for one compound, MCL 209 (max 84+/-19 blinks/15 min) and plateaued at the highest doses, suggestive of partial agonist effects. Additionally, the agonist MCL 206, like the D(1)antagonist SCH 23390, antagonized the effects of SKF 82958 on eye blinking. The findings suggest that D(1)-like agonists increase eye blinking in rats and that these effects may provide a simple measure that can be used to distinguish partial D(1)-like ligands. Further studies with novel D(1)-like partial agonists may be useful in the development of pharmacotherapies for cocaine abuse.
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http://dx.doi.org/10.1097/FBP.0b013e3282f14ee6DOI Listing
December 2007

R-(-)-N-alkyl-11-hydroxy-10-hydroxymethyl- and 10-methyl-aporphines as 5-HT1A receptor ligands.

Bioorg Med Chem Lett 2007 Aug 23;17(15):4128-30. Epub 2007 May 23.

Alcohol Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.

Several N-substituted-11-hydroxy-10-hydroxymethyl- and 11-hydroxy-10-methylaporphines were synthesized and their binding affinities at dopamine D(1) and D(2) receptors and serotonin 5-HT(1A) and 5-HT(2A) receptors in rat forebrain tissue were evaluated. Tested compounds displayed moderate to high affinity to 5-HT(1A) receptors but low affinity to D(1) and D(2) receptors. The most potent novel 5-HT(1A) agent was R-(-)-N-methyl-10-hydroxymethyl-11-hydroxyaporphine.
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http://dx.doi.org/10.1016/j.bmcl.2007.05.057DOI Listing
August 2007
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