Receptor specificity of the 5HT2 receptor antagonist,LY53857

LY53857 is a potent antagonist at vascular 5HT₂ receptors that lacks prominent α₁ or dopamine antagonist activity. The present report investigates the interaction of LY53857 with other receptor mechanisms. LY53857 showed no agonist activity in the guinea pig trachea, guinea pig atria, guinea pig ileum, or rat vas deferens. Furthermore, LY53857 did not antagonize histamine (H₁) or β₂ receptors in the guinea pig trachea, β₁ in the guinea pig atria, muscarinic, or angiotensin I receptors in the guinea pig ileum. However, LY53857 did block α₂ receptors (?log K_B = 6.51) as determined by antagonism of the inhibitory effects of the selective β₂ agonist, UK-14,304, on the twitch response in the guinea pig ileum. LY53857 antagonized β₂ receptors at concentrations approximately 6000-fold higher than necessary to block 5HT₂ receptors (?log K_B = 10.3). Taken in concert, these data support the contention that LY53857 is a highly selective antagonist of 5HT₂ receptors, and that LY53857 is a useful tool with which to probe 5HT₂ receptors and serotonergic mechanisms.