Human fat cell alpha-2 adrenoceptors. II. Comparative study of partial and full agonist binding parameters using [3H]clonidine and [3H]UK-14,304.
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.
Galitzky
J
J
Institut National de la Santé et de la Recherche Médicale (INSERM U.317), Universté Paul Sabatier, Toulouse, France.
Lafontan
M
M
Paris
H
H
Berlan
M
M
D000273:Adipose Tissue / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000378:metabolism*; D000494:Allosteric Regulation; D001667:Binding, Competitive; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000378:metabolism*; D005033:Ethylmaleimide / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D011810:Quinoxalines / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D015016:Yohimbine / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D006165:Guanylyl Imidodiphosphate; D000068438:Brimonidine Tartrate; D019204:GTP-Binding Proteins; D008274:Magnesium; D003000:Clonidine; D005033:Ethylmaleimide