Binding of O-alkyl derivatives of serotonin at human 5-HT1D beta receptors.
In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1D beta receptors (Ki < 5 nM) but demonstrate less than 50-fold selectivity relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT1A receptors whereas groups longer than nine carbon atoms lead to compounds with reduced affinity at 5-HT1D beta receptors. 5-(Nonyloxy)tryptamine (10) represents a compound with optimal 5-HT1D beta affinity (Ki = 1 nM) and selectivity (> 300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1D beta Ki = 2.3 nM) but with greater (i.e, 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or beta-carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1D beta versus 5-HT1D alpha sites; nevertheless, compounds 10 (recently shown to have as a 5-HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.
Glennon
R A
RA
Department of Medicinal Chemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540, USA.
Hong
S S
SS
Bondarev
M
M
Law
H
H
Dukat
M
M
Rakhi
S
S
Power
P
P
Fan
E
E
Kinneau
D
D
Kamboj
R
R
Teitler
M
M
Herrick-Davis
K
K
Smith
C
C
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000378:metabolism*; D011994:Recombinant Proteins; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D014363:Tryptamines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D012701:Serotonin; D018170:Sumatriptan