Novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines as potent and selective agonists of the 5-HT2C receptor.

A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.

Discovery of a lead series of potent benzodiazepine 5-HT2C receptor agonists with high selectivity in functional and binding assays.

A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.

Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor.

The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.

Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.

The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.

Cognitive enhancing properties and tolerability of cholinergic agents in mice: a comparative study of nicotine, donepezil, and SIB-1553A, a subtype-selective ligand for nicotinic acetylcholine receptors.

Several studies have demonstrated the importance of nicotinic mechanisms in the pathophysiology of neurodegenerative and cognitive disorders, warranting the search and development of novel nicotinic ligands as potential therapeutic agents. The present study was designed to assess whether the subtype-selective nicotinic acetylcholine receptor (nAChR) ligand SIB-1553A [(+/-)-4-([2-(1-methyl-2-pyrrolidinyl)ethyl]thio)phenol hydrochloride], with predominant agonist activity at beta4 subunit-containing human nAChRs, and no activity at muscle nAChR subtypes, could enhance cognitive performance in rodents with a more desirable safety/tolerability profile as compared to the nonselective prototypic nAChR ligand nicotine. SIB-1553A was equi-efficacious to nicotine in improving working memory performance in scopolamine-treated mice as measured by increased alternation in a T-maze, and was more efficacious than nicotine in improving the baseline cognitive performance of aged mice. This effect on working memory was confirmed in a delayed nonmatching to place task using the eight-arm radial maze. SIB-1553A produced dose-dependent side effects (ie motor deficits and seizures), although these effects were observed at doses 12 to 640-fold above those required to increase cognitive performance. Overall, SIB-1553A was significantly less potent than nicotine in eliciting these undesirable effects. Thus, the subtype-selective profile of SIB-1553A appears to translate into a more efficacious and better tolerated nAChR ligand as compared to nicotine. In the present studies, cognitive enhancement induced by SIB-1553A was similar in magnitude to that produced by the clinically efficacious acetylcholinesterase inhibitor donepezil. Taken together, the present data confirm the importance of nAChR subtypes in modulating cognitive processes, and suggest that activation of nAChR subtypes by selective nAChR ligands may be a viable approach to enhance cognitive performance.

Pharmacological characterization of SIB-1663, a conformationally rigid analog of nicotine.

SIB-1663 ([+/-]-7-methoxy-2,3,3a,4,5,6,9b-hexahydro-1H-pyrrolo-[3,2h]-isoquinoline) is a conformationally restricted analog of nicotine (NIC). SIB-1663 exhibited modest affinities to cholinergic receptors (K(i) values displacing the binding of [(3)H]-nicotine (NIC) and [(3)H]-quinuclinidylbenzilate (QNB) binding were 1.0+/-0.3 and 2.6+/-0.3 microM, respectively) with no appreciable affinity to nearly 40 other receptors. SIB-1663 selectively activated alpha2beta4 and alpha4beta4 human recombinant neuronal nicotinic acetylcholine receptors (nAChRs) with no appreciable activation of alpha4beta2 nAChRs, the presumed high-affinity nAChRs in rodent brain. These properties led us to examine profile of SIB-1663 in native preparations. SIB-1663 increased DA release from the rat striatum (STR) and olfactory tubercles and NE release from hippocampus, thalamus and prefrontal cortex (PFC). SIB-1663 was equiefficacious to NIC in STR-DA and PFC-NE release assays and less efficacious than NIC in other release assays. SIB-1663 appeared to be partial agonist in the hippocampal NE release assay. SIB-1663-induced neurotransmitter release in vitro was relatively insensitive to the nAChR antagonists, mecamylamine (MEC) or dihydro-beta-erythroidine (DHbetaE) providing equivocal evidence for nAChR activity. SIB-1663 (3-30 mg/kg, s.c.) increased locomotor activity in naive rats in a novel environment, increased ipsilateral turning in rats with unilateral 6-OHDA nigrostriatal lesion and increased withdrawal latencies in the tail-flick assay. The in vivo effects of SIB-1663 in these assays showed varying degrees of sensitivity to nAChR antagonists in that the locomotor activity and turning behavior of SIB-1663 were partially sensitive to MEC, whereas the antinociceptive activity was completely sensitive to MEC. In addition, SIB-1663 (s.c. or i.c.v.) attenuated antinociceptive activity NIC given by the same route suggesting a partial agonist activity. SIB-1663 also increased the retention of avoidance learning in normal rats when administered immediately after the acquisition session. These data indicate that SIB-1663, a conformationally restricted analog of NIC, with distinct nAChR subtype selectivity from NIC exhibits contrasting pharmacology with some of its in vivo actions involving nAChRs.

Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity.

We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.