| Recent understanding of the clinical importance of the histamine H 1 G protein-coupled receptor (GPCR) in brain suggests the pharmacotherapeutic potential of H1 agonists in neuropsychiatric and neurodegenerative diseases. This thesis reports the synthesis, pharmacology, and molecular modeling studies of novel (+/-)-2-dimethylamino-6-phenyl-1,2,3,4-tetrahydronaphthalene derivatives (6-APTs), as ligands for the human histamine H1 GPCR, and, its close phylogenetic relatives, the serotonin 5HT2A and 5HT2C GPCRs.; Five novel 6-APTs (meta-substituted on the 6-phenyl moiety with H, Br, Cl, CF3, or OCH3) were synthesized starting from the appropriate phenylacetic acid derivatives, which were cyclized to the corresponding 2-tetralones and coupled with phenylboronic acids to yield biaryl tetralones, that underwent reductive amination to the products. Affinity (Ki) for human H1, 5HT2A, and 5HT 2C receptors was assessed by radioreceptor assays using membranes prepared from CHO cells stably transfected and expressing the appropriate cDNAs. H 1 receptor Ki values for the 6-APTs varied 100-fold, ranging from 0.1 muM for Br-6-APT to 10 muM for the parent 6-APT. The 6-APTs did not demonstrate H1 receptor agonist activity regarding stimulation of phospholipase C/inositol phosphate (PLC/IP) and adenylyl cyclase/cAMP signaling in CHO-H1 cells. CF3-6-APT, however, did stimulate PLC/IP formation by a non H1 receptor mechanism in CHO-K1 cells, apparently via direct activation of PLC. Br-6-APT, (highest H1 affinity) was identified as a novel competitive H1 receptor antagonist (KB = 12.0 nM). A molecular model was developed to predict ligand structural parameters for binding to human H1 receptors, using 75 H1 receptor ligands (including APTs) in a comparative molecular field analysis (CoMFA) study. The model predicted H1 affinity values with R2 = 0.788, indicating a higher degree of external predictability in comparison to a previously reported H1 receptor CoMFA model. At 5HT2 receptors, Cl-6-APT and a related 5-APT, demonstrated relatively potent and selective 5HT2C (over 5HT2A) receptor agonist activity to stimulate PLC/IP signaling.; In summary, results indicate the 6-APT molecular scaffold is not optimal for development of high affinity H1 receptor agonists. The 6-APTs, however, do represent an important new class of selective agonists for the 5-HT2C receptor, recently proposed as novel pharmacotherapeutic target in obsessive-compulsive and eating disorders. |
