INTERACTION OF D-TUBOCURARINE ANALOGS WITH THE 5HT(3) RECEPTOR

D-Tubocurarine is a potent competitive antagonist of two members of th e ligand-gated ion channel family, the muscle-type nicotinic acetylcho line receptor (AChR) and serotonin type-3 receptor (5HT(3)R). We have used a series of analogs of D-tubocurarine to determine the effects of methylation, stereoisomerization and halogenation on the interaction of D-tubocurarine with the 5HT(3)R. The affinities of the analogs for the 5HT(3)R span a 200-fold concentration range and fall into three br oad groups. The first group, with affinity constants (K-i) < 150 nM, c onsists of D-tubocurarine and analogs modified at the nitrogens or 7' hydroxyl. The fact that these compounds all have high affinity for the 5HT(3)R suggests that these portions of the ligand do not make intera ctions with the receptor that are critical for high-affinity binding. The second group, with K-i's in the 1-5 mu M range, consists of analog s modified at the 12'-hydroxyl or the adjacent 13'-carbon, which sugge sts that this portion of the ligand makes interactions that are import ant for high-affinity binding. The third, very low affinity, group is a compound with altered stereoconfiguration at the 1 carbon, demonstra ting the importance of proper configuration of the antagonist in ligan d-receptor interactions. For the most part, this pattern of selectivit y is similar to that for the AChR, suggesting that the structures of t he ligand-binding sites of these two receptors share common structural features. (C) 1998 Elsevier Science Ltd. All rights reserved.