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Functionally rightward-shifted serotonin 5-HT2C receptor agonists are inactive at 5-HT2A and 5-HT2B receptors

Functionally rightward-shifted serotonin 5-HT2C receptor agonists are inactive at 5-HT2A and 5-HT2B receptors

Society for Neuroscience Abstracts 27(1): 693

The serotonin 5-HT2 receptor family is composed of the 5-HT2A, 5-HT2B and 5-HT2C receptors. All three receptors have been shown to classically couple to inositol phosphate metabolism via Gq and phospholipase C. Compounds that are agonists at one receptor are usually agonists at the other receptor subtypes, likely due to structural similarities within the agonist binding sites. We have previously reported that the 5-HT2C receptor agonist IL810 exhibits a significantly rightward-shifted EC50 for the stimulation of inositol phosphates (2270 nM) relative to its Ki for the 5-HT2C receptor (1.6 nM), but is potent and efficacious in stimulating cGMP production (4.3 nM). Here we present additional data that IL810 and the similarly rightward shifted compound IL639 (Ki 4.0 nM, EC50 464 nM) do not stimulate inositol phosphate accumulation in cells expressing either the 5-HT2A or 5-HT2B receptor. In contrast the more potent activators of inositol phosphate accumulation, SK432 (Ki 1.0 nM, EC50 16 nM) and IK264 (Ki 11.0 nM, EC50 nM), are agonists at both 5-HT2A (SK432, EC50 209 nM) and 5-HT2B receptors (IK264, EC50 241 nM). The data demonstrate that compounds which preferentially activate alternatively coupled 5-HT2C receptors do not activate 5-HT2B and 5-HT2A receptors. This work suggests that those compounds that do not preferentially signal through Gq-mediated inositol phosphate accumulation may be functionally selective 5-HT2C receptor agonists vs. the other 5-HT2 receptor types.

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