Agonist action of indole derivatives at 5-HT1-like, 5-HT3, and 5HT4 receptors in vitro.
1. The potency of indole analogues has been studied, in vitro, at 5-hydroxytryptamine4 (5-HT4) receptors mediating contractions of guinea-pig ileum and relaxation of rat oesophagus. These have been compared to other 5-HT receptors in canine saphenous vein (5-HT1-like), rabbit aorta (5-HT2), and guinea-pig ileum (5-HT3). 2. At receptors mediating 5-HT4 responses in ileum and oesophagus, the rank orders of potency were similar. These rank orders differed from those observed at 5-HT1-like, 5-HT2, and 5-HT3 receptors. In particular, 5-hydroxy N,N, dimethyltryptamine but not 5-methoxy N,N, dimethyltryptamine acted as agonists at 5-HT4 receptors. At 5-HT1-like, 5-HT2 and 5-HT3 receptors these compounds were both active. 3. The 5-HT receptors mediating contractions of canine cephalic vein exhibited a rank order profile similar to that observed at receptors mediating contractions of canine saphenous vein, suggesting stimulation of a 5-HT1-like receptor. 4. The rank order of potency of the substituted indoles differed at 5-HT receptors mediating responses in canine saphenous vein, rabbit aorta and guinea-pig ileum (determined in the presence of 5-methoxytryptamine to desensitize 5-HT4 receptors), suggesting the presence of three distinct receptors. Indeed, at 5-HT3 receptors in the ileum, only three agonists (5-HT, 2-methyl-5-HT and 5-hydroxy N,N, dimethyltryptamine) elicited a response, while all remaining compounds were inactive. 5. It is concluded that rank orders of indole potency can prove useful in the delineation of 5-HT subtypes and together with differential antagonist affinities support the existence of four 5-HT receptor subtypes.
Eglen
R M
RM
Institute of Pharmacology, Syntex Research, Palo Alto, California 94304.
Perkins
L A
LA
Walsh
L K
LK
Whiting
R L
RL
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002550:Cerebral Veins / Q000187:drug effects; D004285:Dogs; D004947:Esophagus / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D011985:Receptors, Serotonin / Q000187:drug effects*; D012501:Saphenous Vein / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D007211:Indoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists