Synthesis, histamine H1 receptor pharmacology, and quantitative structure-affinity analysis of 2-dimethylamino-5-phenyl-1,2,3,4-tetrahydronaphthalenes

This thesis reports the synthesis, receptor affinity and functional pharmacology, and quantitative structure-affinity analysis of (+/-)-2-dimethylamino-5-phenyl-1,2,3,4-tetrahydronaphthalene (5-APT) and its meta-substituted (Cl, CF3, OMe) derivatives. The molecular scaffold of 5-APTs is a hybrid structure of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalene (PAT)-type and 2-phenylhistamine-type H1 agonists, intended to probe molecular determinants required for binding and activation of the human histamine H1 G protein-coupled receptor (GPCR).; The 5-APTs were synthesized by coupling 5-bromo-1-tetralone to the appropriate meta-substituted phenylboronic acid. After transposing the ketone to the 2-position of the substituted naphthalene ring, reductive amination with dimethylamine afforded the desired 5-APT.; The H1 affinity (Ki) of the 5-APTs was ∼3--6 muM, using membranes prepared from CHO cells that stably express human H1 receptor cDNA (CHO-H1). H1 affinity of the 5-APTs is similar to 2-phenylhistamines, but much lower than PATS. 5-APTs stimulated PLC/[ 3H]-IP formation, but not cAMP formation, in CHO-H1 cells. About 25% of the [3H]-IP increase appears to occur via activation of H1 receptors and the balance may be through direct activation of G-protein. 5-APT binds with relatively much higher affinity (Ki ∼30--800 nM) at muscarinicM1--M5 and serotonin 5-HT 2A and 5-HT2C receptors, GPCRs that are phylogenetically closely related to H1. 5-APT acted as a selective agonist at 5-HT 2C (but not 5-HT2A or muscarinic) receptors to stimulate PLC/[3H]-IP formation.; A quantitative structure-affinity relationship (QSAR) was developed for 5-APT, PAT-type, and non-PAT H1 ligands. The QSAR comparative molecular field analysis (CoMFA) model gave a q2 > 0.5 and predictive R2 > 0.6, indicating a high degree of internal and external predictability of H1 affinity, within a newly expanded probed H1 receptor space.; Overall, results indicate that the 5-APT structural scaffold is not optimal for development of high affinity, selective H1 receptor agonists. The 5-APT molecular scaffold, however, does appear to be useful for development of 5-HT 2C receptor agonists that may find pharmacotherapeutic applications in neuropsychiatric disorders.