Seven transmembrane receptor (7TMR) responses are modulated by orthosteric and allosteric ligands to great therapeutic advantage. Here we introduce a unique class of negative allosteric modulator (NAM) - the positive allosteric modulator (PAM)-antagonist - that increases the affinity of the receptor for the agonist but concomitantly decreases agonist efficacy when cobound. Notably, the reciprocation of allosteric energy causes the orthosteric agonist to increase the affinity of the receptor for the PAM-antagonist; thus, this modulator seeks out and destroys agonist-bound receptor complexes. When contrasted with standard orthosteric and allosteric antagonists it is clear that PAM-antagonists are uniquely well suited to reversing ongoing persistent agonism and provide favorable target coverage in vivo. Specifically, the therapeutic application of PAM-antagonists to reverse pathological overactivation (e.g., endothelin vasoconstriction) is emphasized.
Keywords: drug discovery; negative allosteric modulation; receptor antagonism; receptor theory; selective drug antagonism.
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