title: Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes.
abstract: 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 H1 receptor. The 5-APTs have 2- to 4-fold higher H1 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 H1 affinity. In contrast, analogous meta-substitution for the 6-APTs increases H1 affinity up to 100-fold. The new APTs do not activate H1 receptor-linked intracellular signaling and apparently are competitive H1 antagonists. A new model that establishes structural parameters for binding to the human H1 receptor by APTs and other ligands was developed using 3-D QSAR (CoMFA). The model predicts H1 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-HT2A and 5-HT2C receptors, which are phylogenetically closely related to the H1 receptor. 5-APT and m-Cl-6-APT were identified as novel agonists that selectively activate 5-HT2C receptors. It is concluded that the lipophilic (brain-penetrating) APT molecular scaffold may have pharmacotherapeutic potential in neuropsychiatric diseases.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
authors.forename: Ola M
authors.initials: OM
authors.lastname: Ghoneim
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Legere
authors.forename: Alexander
authors.initials: A
authors.lastname: Golbraikh
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006634:Histamine H1 Antagonists / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008744:Methylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D011738:Pyrilamine / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects; D013329:Structure-Activity Relationship; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D006634:Histamine H1 Antagonists; D007202:Indicators and Reagents; D007295:Inositol Phosphates; D008024:Ligands; D008744:Methylamines; D009281:Naphthalenes; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; D010738:Type C Phospholipases; D011738:Pyrilamine