| Novel 4-phenyl-N,N-dimethyl-1,2,3,4-tetrahydroanphthalene-2-amine (phenylaminotetrahydronaphthalin; PAT) analogs synthesized in our laboratories have been shown to specifically activate the human serotonin 5-HT2C receptors while acting as antagonists/inverse agonists at 5-HT2A and 5-HT2B receptors. This unique 5-HT2 pharmacology was hypothesized to translate to efficacy in animal models of psychosis. The specific aims here were to characterize the molecular determinants for 5-HT 2 affinity of new PAT derivatives synthesized before and during the course of this thesis research (Aim 1), characterize the 5-HT2 functional pharmacology of PATs meeting minimum affinity criteria (Aim 2), and, determine if PATs that demonstrate 5-HT2C specific agonism together with 5-HT2A/2B antagonism/inverse agonism translate in preclinical studies to efficacious compounds to treat psychoses (Aim 3).;Some noteworthy results are that meta- and para-substitution of the 4-phenyl substituent impacted stereoselective high affinity of especially the trans-PAT analogs across 5-HT2 receptors. For example, the (2S,4 R)-(--)-enantiomer usually demonstrated highest affinity across 5-HT2 receptors regarding meta-substituted trans-PATs, while, the (2R,4S)-(+)-enantiomer usually demonstrated highest affinity across 5-HT2 receptors regarding para-substituted trans-PATs. Results from ligand docking and molecular modeling studies conducted by a collaborator suggest that a conserved (across 5-HT2 receptors) serine S5.43 residue in the fifth transmembrane domain impacts binding of the 4-para-substituted-PATs differently than for the corresponding 4-(meta-substituted)-PATs. The (2S,4R)-(--)-trans-(meta -chloro and meta-bromo)-PAT analogs had the highest affinity across 5-HT2 receptors and these analogs also demonstrated highest potency and efficacy regarding 5-HT2C agonism together with 5-HT2A/2B antagonism/inverse agonism in functional studies using human recombinant 5-HT2 receptors expressed in HEK clonal cells. Substitutions at the 6- and/or 7-position of tetrahydronaphthyl moiety, with or without concomitant halogen substitution at the 4-meta-phenyl-position, did not provide analogs with enhanced potency or efficacy regarding functional activity. Accordingly, the trans-4-(meta-chloro and meta-bromo)-PATs were selected for study in translational studies that also included the trans-4-(para-chloro)-PATs for comparison.;The PATs were assessed in three different rodent psycholocomotor models of psychosis, which encompass the dopaminergic, glutamatergic and serotonergic neurotransmitter dysfunction currently thought to underlie the pathophysiology of human psychoses. The (2S,4R)-(--)- trans-4-(meta-Cl and meta-Br)-PAT analogs demonstrated superior potency compared to (2S,4 R)-(--)-trans- and (2R,4 S)-(+)-trans-4-(para-Cl)-PAT analogs, suggesting that the in vitro medicinal chemistry structure-activity relationship accurately translated to predict the preclinical activity of PATs as antipsychotic drugs. |
