Binding of O-Alkyl Derivatives of Serotonin at Human 5-HT1Dβ Receptors

Abstract

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.

5-HT Prolongs Ventral Root Bursting Via Presynaptic Inhibition of Synaptic Activity During Fictive Locomotion in Lamprey

“…Two pressure ejection pipettes, filled with either 5-HT (300 M) or L694-247 (1 M), were positioned within 1 mm of the recording pipette. To compensate for dilution of L694-247 during pressure ejection, we used a concentration 100-fold higher than the K d (Glennon et al 1996) (10-fold higher than a dose that significantly inhibits synaptic transmission, see Fig. 2).…”

Frequency-Dependent Modulation of Retinogeniculate Transmission by Serotonin

“…The robust effects of 5-HT 1 receptor agonist and antagonist, 5-CT and cyanopindolol, respectively, at the retinogeniculate synapse suggested the involvement of this subclass of receptors. To distinguish between 5-HT 1A and 5-HT 1B receptors, we first examined the effects 5 M 5-nonyloxytryptamine (5-NOT), an agonist with higher selectivity for the 5-HT 1B over the 5-HT 1A receptor (Glennon et al, 1996). Nonyloxytryptamine (5 M) significantly inhibited the peak amplitude of evoked EPSCs to 48.8 Ϯ 7.5% of control (n ϭ 4; p Ͻ 0.05, paired t test) (Fig.…”

Characterization of metabolic phenotypes of mice lacking GPR61, an orphan G-protein coupled receptor

“…1 nM) and has moderate affinity for 5-HT1A receptors (Ki = approx. 600 nM) (Glennon et al, 1994(Glennon et al, , 1996. Because GPR61 shows high sequence similarity to biogenic amine receptors, we tested the ability of biogenic amines and their metabolites to function as ligands for cells stably expressing GPR61 in preliminary experiments.…”