Improvement in glucocorticoid receptor binding affinity concomitant to shift from antagonist to agonist activity in a series of 17 beta-carboxamide derivatives of dexamethasone.

Modification of the 17 beta-side chain of the synthetic glucocorticoid agonist dexamethasone by periodic oxidation and subsequent coupling to various primary amines yield secondary 17 beta-carboxamide derivatives displaying antiglucocorticoid activity in vitro, but not in vivo. To obtain more potent antiglucocorticoids, new secondary and tertiary 17 beta-carboxamide derivatives were synthesized. Although they displayed an improved affinity for the glucocorticoid receptor in rat thymus cytosol and antiglucocorticoid activity in rat hepatoma (HTC) cells, these new compounds were again devoid of in vivo antiglucocorticoid activity in the rat. Moreover, the increase in receptor binding affinity was correlated for most compounds with the appearance of a partial agonist activity in HTC cells. The tertiary 17 beta-carboxamide derivative DX diMe displayed the highest affinity but was also a partial agonist in vivo. Kinetic studies with several tritiated 17 beta-carboxamide derivatives showed that they had association rate constants similar to that of dexamethasone, but different dissociation rate constants. The rapid dissociation of the compounds displaying antiglucocorticoid activity contrasted with the slow dissociation of DX diMe. Therefore, antiglucocorticoid activity in the 17 beta-carboxamide series is probably related to the formation of rapidly dissociating glucocorticoid receptor-ligand complexes that are unable to undergo the transformation step.