Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: Potential utility as antipsychotic medications

Abstract

Background Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an antipsychotic drug, without liability for weight gain. Methods The novel compounds (+)- and (−)-trans-4-(4′-chlorophenyl)-N,N-dimethyl-2-aminotetralin (p-Cl-PAT) were synthesized, characterized in vitro for affinity and functional activity at human 5HT2 receptors, and administered by intraperitoneal (i.p.) and oral (gavage) routes to mice in behavioral paradigms that assessed antipsychotic efficacy and effects on feeding behavior. Results (+)- and (−)-p-Cl-PAT activated 5HT2C receptors, with (+)-p-Cl-PAT being 12-times more potent, consistent with its higher affinity across 5HT2 receptors. Neither p-Cl-PAT enantiomer activated 5HT2A or 5HT2B receptors at concentrations up to 300-times greater than their respective affinity (Ki), and (+)-p-Cl-PAT was shown to be a 5HT2A competitive antagonist. When administered i.p. or orally, (+)- and (−)-p-Cl-PAT attenuated the head-twitch response (HTR) in mice elicited by the 5HT2 agonist (−)-2,5-dimethoxy-4-iodoamphetamine (DOI) and reduced intake of a highly palatable food in non-food-deprived mice, with (+)-p-Cl-PAT being more potent across behavioral assays. Conclusions The novel in vitro pharmacology of (+)-p-Cl-PAT (5HT2A antagonism/5HT2C agonism without activation of 5HT2B) translated in vivo to an orally-active drug candidate with preclinical efficacy to treat psychoses without liability for weight gain.

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

“…This effect has been noted for related trans-4-phenyl-2-dimethylaminotetralins (Canal et al, 2013;Morgan et al, 2013). In contrast, clozapine substantially decreased locomotion below levels of vehicle-treated animals when administered alone or in combination with DOI, mirroring its sedative effects in humans, a side effect that may translate to the oftreported "empty-headed" sensation caused by available antipsychotic drugs (Moritz et al, 2013).…”

Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

“…For other PATs, the enantiomer that demonstrates highest affinity at h5-HT2A reliably translates as the more potent and efficacious enantiomer in mouse neurobehavioral models of 5-HT2 receptor activation, including the DOI-elicited HTR (Canal et al, 2013;Morgan et al, 2013). In addition, PAT enantiomers generally retain their affinity (K i ) differences across 5-HT2 subtypes, e.g., if one enantiomer is more potent at 5-HT2A, it is predictably more potent at 5-HT2B and 5-HT2C, probably because of relatively high sequence homology (∼75%) in 5-HT2 family TMDs.…”

“…Drug discovery programs targeting 5-HT2 receptors are focused on treating psychosis (5-HT2A antagonists), sleep disorders (5-HT2A antagonists), cluster headaches (5-HT2 agonists), anxiety (5-HT2B/2C antagonists), and obesity (5-HT2C agonists) (Sewell et al, 2006;Abbas and Roth, 2008;Smith et al, 2010). In addition, compounds with combined 5-HT2C agonist plus 5-HT2A/2B antagonist activity, similar to certain trans-4-phenyl-2-dimethylaminotetralins (PATs), may be useful for treating substance abuse and other compulsive behavioral disorders Canal et al, 2013;Cunningham et al, 2013;Higgins et al, 2013;Morgan et al, 2013).…”

“…Using a structure-based drug design approach, novel PATs targeting 5-HT2 receptors are being developed to treat compulsive behavioral and other neuropsychiatric disorders (Rowland et al, 2008;Booth et al, 2009;Canal et al, 2013;Morgan et al, 2013). Reported here are results from in silico m5-HT2A and h5-HT2A molecular modeling/ligand docking studies, in vitro molecular pharmacology studies, and in vivo neurobehavioral studies using the DOI-elicited HTR model for the trans-(2)-and trans-(1)-enantiomers of two PAT-type drug candidates, 6-OH-7-Cl-PAT and 6-OMe-7-Cl-PAT (Fig.…”

From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists

“…Whether this example of functional selectivity can be exploited for therapeutic gain is an intriguing possibility. A second future development may be the design of drugs having a mixed target property, for example mixed 5-HT 2C agonist/5-HT 2A antagonism (see [71,101]). An alternative drug approach is through direct targeting of proteins interacting with the 5-HT 2C receptor, for example PTEN [55,102].…”