Publications by authors named "Jamin Boggs"

23 Publications

  • Page 1 of 1

Pharmacological blockade of serotonin 5-HT₇ receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission.

PLoS One 2011 20;6(6):e20210. Epub 2011 Jun 20.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, California, United States of America.

The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020210PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119073PMC
October 2011

Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement.

Psychopharmacology (Berl) 2011 May 22;215(1):191-203. Epub 2010 Dec 22.

Neuroscience, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA 92121, USA.

Rationale: Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.

Objective: The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.

Methods: Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.

Results: Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures.

Conclusions: Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.
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http://dx.doi.org/10.1007/s00213-010-2127-xDOI Listing
May 2011

JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats.

Psychopharmacology (Berl) 2011 Apr 18;214(4):829-41. Epub 2010 Nov 18.

Bristol Myers-Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.

Rationale: A few recent studies suggest that brain histamine levels and signaling via H(3) receptors play an important role in modulation of alcohol stimulation and reward in rodents.

Objective: The present study characterized the effects of a novel, selective, and brain penetrant H(3) receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats.

Methods: The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats.

Results: Subcutaneous administration of the selective H(3) receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens.

Conclusions: These results indicate that blockade of H(3) receptor should be considered as a new attractive mechanism for the treatment of alcoholism.
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http://dx.doi.org/10.1007/s00213-010-2092-4DOI Listing
April 2011

Indole- and benzothiophene-based histamine H3 antagonists.

Bioorg Med Chem Lett 2010 Nov 27;20(21):6226-30. Epub 2010 Aug 27.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121-1126, United States.

Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
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http://dx.doi.org/10.1016/j.bmcl.2010.08.103DOI Listing
November 2010

Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists.

Eur J Med Chem 2009 Nov 16;44(11):4413-25. Epub 2009 Jun 16.

Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States.

A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.
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http://dx.doi.org/10.1016/j.ejmech.2009.06.007DOI Listing
November 2009

Pharmacokinetics and pharmacodynamics of norfluoxetine in rats: Increasing extracellular serotonin level in the frontal cortex.

Pharmacol Biochem Behav 2009 May 5;92(3):469-73. Epub 2009 Feb 5.

Johnson and Johnson Pharmaceutical Research and Development, L. L. C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Norfluoxetine is the most important active metabolite of the widely used antidepressant fluoxetine. Although the pharmacokinetics/pharmacodynamics (PK/PD) relationship and neurochemical profile of fluoxetine is well characterized in human and in animals, little is known about the effect of its metabolite. The aim of this study was to characterize extracellular level of serotonin (5-hydroxytryptamine, 5-HT)-time profile of norfluoxetine after acute administration over 18 h post dose and to establish the relationship between this pharmacodynamic (PD) profile and its pharmacokinetic (PK) properties. Following subcutaneous administration of fluoxetine in rats, plasma and brain PK of fluoxetine and norfluoxetine were monitored respectively by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The extracellular level of 5-HT in the frontal cortex was measured by microdialysis as a PD endpoint. Norfluoxetine when directly administrated to rats caused a significant increase in extracellular level of 5-HT in the frontal cortex and maintained for 18 h. This result is correlated well with higher plasma and brain concentration and longer plasma and brain retention time of norfluoxetine. Our results showed that norfluoxetine contributes to 5-HT transporter inhibition and extends fluoxetine efficacy.
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http://dx.doi.org/10.1016/j.pbb.2009.01.023DOI Listing
May 2009

JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition.

Neuropharmacology 2009 Jun 2;56(8):1131-7. Epub 2009 Apr 2.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, CA 92121, USA.

Histamine 3 (H(3)) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H(3) receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H(3) receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.
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http://dx.doi.org/10.1016/j.neuropharm.2009.03.011DOI Listing
June 2009

Novel imidazole-based histamine H3 antagonists.

Bioorg Med Chem Lett 2009 Feb 6;19(3):903-7. Epub 2008 Dec 6.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.114DOI Listing
February 2009

In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor.

Eur J Pharmacol 2008 Jun 10;587(1-3):141-6. Epub 2008 Apr 10.

Department of Neuroscience, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.
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http://dx.doi.org/10.1016/j.ejphar.2008.04.008DOI Listing
June 2008

Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity.

Behav Pharmacol 2008 Mar;19(2):153-9

Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia.
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http://dx.doi.org/10.1097/FBP.0b013e3282f62d8cDOI Listing
March 2008

Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2008 Jan 13;18(1):39-43. Epub 2007 Nov 13.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2007.11.016DOI Listing
January 2008

Dual serotonin transporter inhibitor/histamine H3 antagonists: development of rigidified H3 pharmacophores.

Bioorg Med Chem Lett 2007 Oct 15;17(19):5325-9. Epub 2007 Aug 15.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of tetrahydroisoquinolines acting as dual serotonin transporter inhibitor/histamine H(3) antagonists is described. The introduction of polar aromatic spacers as part of the histamine H(3) pharmacophore was explored. A convergent synthesis of the final products allowing late stage introduction of the aromatic side chain was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.08.017DOI Listing
October 2007

Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor.

Eur J Pharmacol 2007 Dec 14;576(1-3):43-54. Epub 2007 Aug 14.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.
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http://dx.doi.org/10.1016/j.ejphar.2007.08.009DOI Listing
December 2007

Benzylamine histamine H(3) antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Sep 26;17(17):4799-803. Epub 2007 Jun 26.

Johnson & Johnson Pharmaceutical Research & Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

The design, synthesis, and in vitro activity of a series of novel 5-ethynyl-2-aryloxybenzylamine-based histamine H(3) ligands that are also serotonin reuptake transporters is described.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.061DOI Listing
September 2007

Pyrrolidino-tetrahydroisoquinolines bearing pendant heterocycles as potent dual H3 antagonist and serotonin transporter inhibitors.

Bioorg Med Chem Lett 2007 Aug 16;17(15):4374-7. Epub 2007 Mar 16.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA.

A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.043DOI Listing
August 2007

Synthesis and biological evaluation of diamine-based histamine H3 antagonists with serotonin reuptake inhibitor activity.

Bioorg Med Chem Lett 2007 Jun 15;17(11):3130-5. Epub 2007 Mar 15.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

The synthesis and structure-activity relationships of a series of novel phenoxyphenyl diamine derivatives with affinity for both the histamine H(3) receptor and the serotonin transporter is described.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.034DOI Listing
June 2007

Pyrrolidino-tetrahydroisoquinolines as potent dual H3 antagonist and serotonin transporter inhibitors.

Bioorg Med Chem Lett 2007 May 4;17(9):2603-7. Epub 2007 Feb 4.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA.

A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.106DOI Listing
May 2007

Novel naphthyridines are histamine H3 antagonists and serotonin reuptake transporter inhibitors.

Bioorg Med Chem Lett 2007 May 4;17(9):2566-9. Epub 2007 Feb 4.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121-1126, USA.

A series of novel tetrahydronaphthyridine-based histamine H(3) ligands that have serotonin reuptake transporter inhibitor activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyridine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.02.006DOI Listing
May 2007

Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Feb 16;17(4):1047-51. Epub 2006 Nov 16.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H(3) ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.036DOI Listing
February 2007

Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore.

Bioorg Med Chem Lett 2007 Feb 2;17(3):702-6. Epub 2006 Nov 2.

Johnson & Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.089DOI Listing
February 2007

Aplysamine-1 and related analogs as histamine H3 receptor antagonists.

Bioorg Med Chem Lett 2006 Feb 21;16(4):897-900. Epub 2005 Nov 21.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Aplysamine-1 (1), a marine natural product, was synthesized and screened for in vitro activity at the human and rat histamine H3 receptors. Aplysamine-1 (1) was found to possess a high binding affinity for the human H3 receptor (Ki = 30+/-4 nM). Synthetic analogs of 1, including des-bromoaplysamine-1 (10) and dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-ethyl}-amine (13), were potent H3 antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2005.11.003DOI Listing
February 2006

4-phenoxypiperidines: potent, conformationally restricted, non-imidazole histamine H3 antagonists.

J Med Chem 2005 Mar;48(6):2229-38

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.
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http://dx.doi.org/10.1021/jm049212nDOI Listing
March 2005

A new class of diamine-based human histamine H3 receptor antagonists: 4-(aminoalkoxy)benzylamines.

J Med Chem 2003 Aug;46(18):3938-44

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H(3) receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be antagonists in a cell-based model of human histamine H(3) receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H(3) receptor antagonist.
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http://dx.doi.org/10.1021/jm030185vDOI Listing
August 2003