2-(1-Naphthyloxy)ethylamines with enhanced affinity for human 5-HT1D beta (h5-HT1B) serotonin receptors

Journal of Medicinal Chemistry
A M IsmaielR A Glennon

Abstract

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.

References

Jun 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·L DemchyshynH B Niznik
Apr 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·R L WeinshankP R Hartig
Apr 1, 1989·Journal of Medicinal Chemistry·M E PiersonR A Glennon
Mar 1, 1994·Neuropharmacology·F G Boess, I L Martin

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Citations

Mar 18, 2010·ChemMedChem·Alessia CarocciCarlo Franchini
Nov 27, 2004·The Journal of Pharmacy and Pharmacology·W R WilliamsP J Nicholls

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