Endocrine Abstracts (2007) 14 S3.4

Ago-allosteric effects of agonist drugs on 7TM receptors and their endogenous hormones – example from the ghrelin receptor

Thue W. Schwartz

University of Copenhagen, Copenhagen, Denmark.

Conventionally, an allosteric modulator is neutral in respect of efficacy and binds to a receptor site distant from the orthosteric site of the endogenous agonist. However, recently compounds being ago-allosteric modulators have been described i.e. compounds acting both as agonists on their own and as enhancers for the endogenous agonists in both increasing agonist potency and often providing additive efficacy - superagonism. The additive efficacy can also be observed with agonists, which are neutral or even negative modulators of the potency of the endogenous ligand. Based on the prevailing dimeric dogma for 7TM receptors, it is proposed that the ago-allosteric modulators often bind in the orthosteric binding site, but – importantly – in the “other” or allosteric protomer of the dimer. Hereby, they can act both as additive co-agonists, and through inter-molecular cooperative effects between the protomers, they may influence the potency of the endogenous agonist. It is of interest that at least some endogenous agonists can only occupy one protomer of a dimeric 7TM receptor complex at a time and thereby they leave the orthosteric binding site in the allosteric protomer free, potentially for binding of exogenous, allosteric modulators. If the allosteric modulator is an agonist, it is an ago-allosteric modulator; if it is neutral, it is a classical enhancer. Molecular mapping in hetero-dimeric class-C receptors, where the endogenous agonist clearly binds only in one protomer, supports the notion that allosteric modulators can act through binding in the “other” protomer. It is suggested that for the in vivo, clinical setting a positive ago-allosteric modulator should be the preferred agonist drug.

T.W. Schwartz & B. Holst: Ago-allosteric modulation and other types of allostery in 7TM dimeric receptors. J. Recept. Signal. Transduct. Res. (2006) 26: 107–128.

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