Interaction of D-tubocurarine analogs with the 5HT3 receptor.
D-Tubocurarine is a potent competitive antagonist of two members of the ligand-gated ion channel family, the muscle-type nicotinic acetylcholine receptor (AChR) and serotonin type-3 receptor (5HT3R). 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 5HT3R. The affinities of the analogs for the 5HT3R span a 200-fold concentration range and fall into three broad groups. The first group, with affinity constants (Ki) < 150 nM, consists of D-tubocurarine and analogs modified at the nitrogens or 7' hydroxyl. The fact that these compounds all have high affinity for the 5HT3R suggests that these portions of the ligand do not make interactions with the receptor that are critical for high-affinity binding. The second group, with Ki's in the 1-5 microM range, consists of analogs modified at the 12'-hydroxyl or the adjacent 13'-carbon, which suggests that this portion of the ligand makes interactions that are important for high-affinity binding. The third, very low affinity, group is a compound with altered stereoconfiguration at the 1 carbon, demonstrating the importance of proper configuration of the antagonist in ligand-receptor interactions. For the most part, this pattern of selectivity is similar to that for the AChR, suggesting that the structures of the ligand-binding sites of these two receptors share common structural features.
Department of Pharmacology, Allegheny University of the Health Sciences, Philadelphia, PA 19129, USA.
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Yan
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Pedersen
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White
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D011985:Receptors, Serotonin / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D013329:Structure-Activity Relationship; D014403:Tubocurarine / Q000031:analogs & derivatives* / Q000378:metabolism
D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D014403:Tubocurarine