Rhodopsin-like (class A) G protein-coupled receptors (GPCRs) are one of the most important classes of drug targets. The discovery that these GPCRs can be allosterically modulated by small drug molecules has opened up new opportunities in drug development. It will allow the drugability of difficult targets, such as GPCRs activated by large (glyco)proteins, or by very polar or highly lipophilic physiological agonists. Receptor subtype selectivity should be more easily achievable with allosteric than with orthosteric ligands. Allosteric modulation will allow a broad spectrum of pharmacological effects largely expanding that of orthosteric ligands. Furthermore, allosteric modulators may show an improved safety profile as compared to orthosteric ligands. Only recently, the explicit search for allosteric modulators has been started for only a few rhodopsin-like GPCRs. The first negative allosteric modulators (allosteric antagonists) of chemokine receptors, maraviroc (CCR5 receptor), used in HIV therapy, and plerixafor (CXCR4 receptor) for stem cell mobilization, have been approved as drugs. The development of allosteric modulators for rhodopsin-like GPCRs as novel drugs is still at an early stage; it appears highly promising.
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