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

Abstract

Serotonin-2C (5-HT 2C ) 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 D 2 receptor antagonism, the 5-HT 2C -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. . 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-HT 2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

“…12 (−)- Trans -PAT functional pharmacology at 5-HT 2 receptors is unique and desirable regarding translation for antipsychotic and other psychotherapeutic activities, without liability for weight gain or cardiotoxicity. 13 Indeed, (−)- trans -PAT demonstrates therapeutic efficacy in rodent models of psychoses 14 and in a rodent compulsive behavioral paradigm that models ‘binge-eating’. 15 We determined previously that (−)- trans -PAT also is a functionally-selective histamine H 1 ligand that activates H 1 receptor-mediated adenylyl cyclase signaling but is an antagonist at H 1 -linked PLC signaling.…”

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

“…The time rate of this biological event was found to echo the clinical latency of efficacy of these antidepressants in humans [Dremencov et al, 2005]. The inhibitory role of the serotonin system toward the dopaminergic one-this being via GABAergic interaction-in the NAs is reminding of the similar balance in the mesolimbic structures [Bankson and Yamamoto, 2004;, where the inhibiting activity of HTR2C over dopaminergic tone is as high that agonists of this receptor have been proposed as antipsychotics [Marquis et al, 2007]. …”

“…Mesolimbic imbalance may be the basis for the rewarding effect of drugs of abuse, as well as it may be one of the neuronal structures whose disrupted regulation may cause the positive symptoms of psychosis. Consistently, dopamine tone is highly involved both in the rewarding system and in the biological mechanisms that are thought to lead to psychosis, to the point that drugs have been designed that tailor these systems [Muller and Carey, 2006;Marquis et al, 2007]. Within the midbrain, there are two groups of neurons that attracted researchers' attention: the periaqueductal gray (PAG) and the substantia nigra (SN).…”

We Need 2C but Not 2B: Developing Serotonin 2C (5‐HT2C) Receptor Agonists for the Treatment of CNS Disorders

“…[6b] The 5-HT 2C receptor is an advantageous target for treating schizophrenia as the activation of it specifically decreases mesolimbic dopamine release without affecting nigrostriatal dopamine. [20] Thus it is predicted to have antipsychotic efficacy while causing few extrapyramidal side effects (EPS). Also, the fact that 5-HT 2C agonists can induce weight loss means that such drugs would likely be devoid of the undesired side effect of weight gain and related metabolic disorders, which have been associated with most currently used antipsychotic drugs.…”

“…WAY-163909 was studied in various preclinical animal models of psychosis, but no clinical trial has been initiated. [17,20] …”