Human fat cell alpha-2 adrenoceptors. II. Comparative study of partial and full agonist binding parameters using...

Binding studies were carried out on human fat cell membranes with the major radioligands available for alpha-2 adrenergic receptor identification: the antagonist [3H]yohimbine, the partial agonist [3H]clonidine ([3H]CLO) and the full agonist radioligand [3H]UK-14,304 ([3H]UK). Binding approaches performed with [3H]UK and [3H]CLO; two imidazoline derivatives exhibiting full and partial agonist properties, respectively, in biological assays clearly indicate that: 1) partial and full agonists label an equivalent number of binding sites corresponding to the high affinity form of the alpha-2 receptor; 2) there is some correlation between the KiH/KiL ratio defined in competition of [3H]yohimbine binding and the intrinsic activity defined in biological assays; 3) differences exist between the dissociation of the full-agonist ([3H]UK) and the partial-agonist ([3H]CLO); 4) the interaction of the full agonist with the alpha-2 receptor promotes the formation of an agonist-alpha-2 receptor-Gi protein complex (HRGi) complex which is more stable than that obtained with the partial agonist as objectivated by the sensitivity to the effects of guanosine 5'-(imido)triphosphate and N-ethylmaleimide; 5) the full-agonist is characterized by a "tight agonist binding" which is not observed with the partial agonist. From a functional point of view, the lower biological activity of the partial alpha-2 agonist could be explained by the formation of more labile HRGi complexes having weaker stability by comparison with the full agonist agents which promote stronger HRGi complexes and sustained activity.