Gary Paul Stack

WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity.

Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D2 receptor antagonism, the 5-HT2C-selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7–30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3–3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity. WAY-163909 (1.7–17 mg/kg i.p.) reversed MK-801 (5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)- and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding, WAY-163909 (0.3–3 mg/kg i.p.; 1–17 mg/kg p.o.) reduced avoidance responding, an effect blocked by the 5-HT2B/2C receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole]. WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1–10 mg/kg i.p.). Thus, the profile of the 5-HT2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.

Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist

The 5-hydroxytryptamine 2C (5-HT2C) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT2C receptor-selective agonist vabicaserin [(−)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT2B receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced 125I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT2C receptor sites in Chinese hamster ovary cell membranes with a Ki value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT2B receptor subtype using [3H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC50, 8 nM; Emax, 100%) in stimulating 5-HT2C receptor-coupled calcium mobilization and exhibited 5-HT2A receptor antagonism and 5-HT2B antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT2B receptors, vabicaserin failed to induce a 5-HT2B receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT2B competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT2B receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT2B receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT2B receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT2C receptor agonist.

WAY-163909, a 5-HT2C agonist, enhances the preclinical potency of current antipsychotics

Introduction5-HT2C agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT2C agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics).ObjectivesThe objectives of these studies were to combine WAY-163909, a selective 5-HT2C agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur.Results and discussionIn mice, co-administration of either haloperidol, or clozapine, produced a significant leftward shift in the ability of WAY-163909 to block apomorphine-induced climbing behavior, without any affect on apomorphine-induced stereotypy or an increased propensity for catalepsy. In the rat-conditioned avoidance model, WAY-163909 was combined with either haloperidol or clozapine at doses that individually produced reductions in avoidance response on the order of 10%, while the combination of WAY-163909 and either of the antipsychotics resulted in a greater than 70% reduction in avoidance, with no evidence of response failures, or pharmacokinetic interaction.ConclusionDoses of either haloperidol or clozapine, that failed to antagonize an MK-801 induced deficit in prepulse inhibition, significantly attenuated the sensory gating deficit when combined with WAY-163909. Data support the notion that 5-HT2C receptor agonists, co-administered with other marketed antipsychotics, allow for dose sparing with a more favorable side-effect profile.

Structure−Activity Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective Norepinephrine Reuptake Inhibitors

Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.

Synthesis, Potency, and in Vivo Evaluation of 2-Piperazin-1-ylquinoline Analogues as Dual Serotonin Reuptake Inhibitors and Serotonin 5-HT1A Receptor Antagonists

On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.

Desvenlafaxine Succinate Identifies Novel Antagonist Binding Determinants in the Human Norepinephrine Transporter

Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657–665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [3H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [3H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3β-(4-iodophenyl)tropane-2β-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS.