GHS-R Inhibitors

Chemical inhibitors of GHS-R function by directly antagonizing the receptor activity, which is typically activated by its endogenous ligand, ghrelin. [D-Lys3]-GHRP-6, JMV 2959, Compound 26, PF-5190457, AZP-531, and YIL781 are all compounds that exhibit their inhibitory effects by binding to the GHS-R, thereby preventing the attachment and subsequent activation by ghrelin. These antagonistic actions ensure that the usual signal transduction initiated by ghrelin's interaction with GHS-R does not occur. For instance, PF-5190457 and AZP-531 are analogs that mimic the structure of ghrelin to occupy the binding site on GHS-R but do not trigger the intracellular responses that ghrelin would, thereby inhibiting the receptor's function. Similarly, YIL781 obstructs the ghrelin signaling pathway by precluding the natural ligand from engaging with the GHS-R.

Additional compounds such as Compound 21 and Epelsiban also function as GHS-R inhibitors by competing with ghrelin for the receptor binding, but without activating the receptor themselves. This competitive inhibition is crucial for blocking the signal cascade that would normally follow ghrelin binding. SPA, a peptidomimetic ghrelin antagonist, and [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-Substance P operate by presenting a structure similar to that of ghrelin, thus preventing the natural hormone from activating GHS-R. Moreover, BIM-28163 adds to this repertoire of GHS-R inhibitors by also engaging the receptor in a manner that obstructs ghrelin's action. This molecule ensurs that the receptor remains in an inactive state, unable to propagate the signaling that would typically result in GHS-R-mediated physiological responses. Each inhibitor, by binding to the GHS-R, ensures that the receptor's functional activity is suppressed, maintaining the receptor in a state that does not support the downstream signaling events normally initiated by ghrelin.