Ismaiel A M, Dukat M, Law H, Kamboj R, Fan E, Lee D K, Mazzocco L, Buekschkens D, Teitler M, Pierson M E, Glennon R A
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA.
J Med Chem. 1997 Dec 19;40(26):4415-9. doi: 10.1021/jm970507t.
Although the beta-adrenergic antagonist propranolol (1) binds at rodent 5-HT1B serotonin receptors, it displays low affinity (Ki > 10,000 nM) for its species homologue 5-HT1D beta (i.e., h5-HT1B) receptors. The structure of propranolol was systematically modified in an attempt to enhance its affinity for the latter population of receptors. Removal of the alkyl hydroxyl group, shortening of the O-alkyl chain from three to two methylene groups, and variation of the terminal amine substituent resulted in compounds, such as N-monomethyl-2-(1-naphthyloxy)-ethylamine (11; Ki = 26 nM), that display significantly higher h5-HT1B affinity than propranolol. Compound 11 was shown to bind equally well at human 5-HT1D alpha (h5-HT1D) receptors (Ki = 34 nM) and was further demonstrated to possess h5-HT1B agonist character in an adenylate cyclase assay. It would appear that such (aryloxy)alkylamines may represent a novel class of 5-HT1D receptor agonists.
