Novel ligands for the human histamine H sub(1) receptor: Synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 19; pp. 6640 - 6658
• Main Authors: Ghoneim, Ola M, Legere, Jacqueline A, Golbraikh, Alexander, Tropsha, Alexander, Booth, Raymond G
• Format: Journal Article
• Language: English
• Published: 01.10.2006
• DOI: 10.1016/j.bmc.2006.05.077
• ISSN: 0968-0896

This paper reports the synthesis of a novel series of (+/-)-2-dimethylamino- 5- and 6-phenyl-1,2,3,4-tetrahydronaphthalene derivatives (5- and 6-APTs), and, corresponding affinity, functional activity, and, molecular modeling studies with regard to drug design targeting the human histamine H sub(1) receptor. The 5- APTs have 2- to 4-fold higher H sub(1) receptor affinity than the endogenous agonist histamine. The chemical nature of a meta-substituent on the 5-APT pendant phenyl moiety does not significantly affect H sub(1) affinity. In contrast, analogous meta-substitution for the 6-APTs increases H sub(1) affinity up to 100-fold. The new APTs do not activate H sub(1) receptor-linked intracellular signaling and apparently are competitive H sub(1) antagonists. A new model that establishes structural parameters for binding to the human H sub(1) receptor by APTs and other ligands was developed using 3-D QSAR (CoMFA). The model predicts H sub(1) ligand binding with a higher degree of external predictability compared to a previously reported model. The APTs also were examined for activity at human serotonin 5-HT sub(2A) and 5-HT sub(2C) receptors, which are phylogenetically closely related to the H sub(1) receptor. 5-APT and m-Cl-6-APT were identified as novel agonists that selectively activate 5-HT sub(2C) receptors. It is concluded that the lipophilic (brain-penetrating) APT molecular scaffold may have pharmacotherapeutic potential in neuropsychiatric diseases.