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
2015
Abstract Syntheses were undertaken of derivatives of (2 S ,4 R )-(−)- trans -4-phenyl- N , N -dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (4-phenyl-2-dimethylaminotetralin, PAT), a stereospecific agonist at the serotonin 5-HT 2C G protein-coupled receptor (GPCR), with inverse agonist activity at 5-HT 2A and 5-HT 2B GPCRs. Molecular changes were made at the PAT C(4)-position, while preserving N , N -dimethyl substitution at the 2-position as well as trans -stereochemistry, structural features previously shown to be optimal for 5-HT 2 binding. Affinities of analogs were determined at recombinant human 5-HT 2 GPCRs in comparison to the phylogenetically closely-related histamine H 1 GPCR, and in silico ligand docking studies were conducted at receptor molecular models to help interpret pharmacological results and guide future ligand design. In most cases, C(4)-substituted PAT analogs exhibited the same stereoselectivity ([−]- trans > [+]- trans ) as the parent PAT across 5-HT 2 and H 1 GPCRs, albeit, with variable receptor selectivity. 4-(4′-substituted)-PAT analogs, however, demonstrated reversed stereoselectivity ([2 S ,4 R ]-[+]- trans > [2 S ,4 R ]-[−]- trans ), with absolute configuration confirmed by single X-ray crystallographic data for the 4-(4′-Cl)-PAT analog. Pharmacological affinity results and computational results herein support further PAT drug development studies and provide a basis for predicting and interpreting translational results, including, for (+)- trans -4-(4′-Cl)-PAT and (−)- trans -4-(3′-Br)-PAT that were previously shown to be more potent and efficacious than their corresponding enantiomers in rodent models of psychoses, psychostimulant-induced behaviors, and compulsive feeding (‘binge-eating’).
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