HT2C Receptor Agonists

It is quite difficult to describe detailed structure-activity relationships for 5-HT2C receptor agonists because a large part of the data has been published in patent applications and refers to compounds that are not directly related structurally. Moreover, interlaboratory comparison of agonist potency and relative efficacy can be difficult (Nilsson 2006). Apart from possible species differences, functional data are often dependent on the in vitro test system used. For example, the potency and efficacy of agonists in functional assays are highly dependent on receptor expression levels. Both receptor-effector coupling and receptor reserve can show large variations from one system and/or tissue to the other. Additionally, the signal transduction characteristics of transfected receptors may be dependent on the identity of the host cell line. Clearly, all these aspects may have a profound impact on the observed functional selectivities over 5-HT2A and 5-HT2B receptors. Generally, functional data are based on measurements of a second messenger response, such as phosphoinositide hydrolysis or increase in intracellular calcium at 5-HT2C, 5-HT2A, and 5-HT2B receptors expressed in the same host cell line. However, several other diverse functional in vitro models (biochemical assays or tissue preparations) have been employed such as phosphoinositide hydrolysis in rat or pig choroid plexus (5-HT2C), phospho-inositide hydrolysis in rat cortex (5-HT2A), effect on human platelet aggregation (5-HT2A), contraction of rat jugular vein (5-HT2A), contraction of the isolated rat tail artery (5-HT2A), and contraction of isolated rat stomach fundus muscle strips (5-HT2B). Yet, another complicating factor is that the 5-HT2C receptor undergoes post-transcriptional mRNA editing. Such editing is associated with different G-protein-coupling efficiencies of the isoforms. In this respect, it has been shown that 5-HT is less potent in stimulating phosphatidylinositol hydrolysis at edited versions of the 5-HT2C receptor than at the nonedited 5-HT2C receptor isoform INI.

All these considerations should be kept in mind when considering the literature data on 5-HT2C receptor agonists.

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