2-(1-Naphthyloxy)ethylamines with enhanced affinity for human 5-HT1D beta (h5-HT1B) serotonin receptors.
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.
Ismaiel
A M
AM
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA.
Dukat
M
M
Law
H
H
Kamboj
R
R
Fan
E
E
Lee
D K
DK
Mazzocco
L
L
Buekschkens
D
D
Teitler
M
M
Pierson
M E
ME
Glennon
R A
RA
D000262:Adenylyl Cyclases / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011433:Propranolol / Q000031:analogs & derivatives* / Q000378:metabolism; D011485:Protein Binding; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000378:metabolism*
C110199:N-monomethyl-2-(1-naphthyloxy)ethylamine; D009281:Naphthalenes; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D011433:Propranolol; D000262:Adenylyl Cyclases