ACTH MSH-LIKE PEPTIDES INHIBIT THE BINDING OF DOPAMINERGIC LIGANDS TO THE DOPAMINE D2 RECEPTOR INVITRO

ACTH-(1-24) decreased the binding of the dopamine D2 receptor agonist, [H-3]N-propylnorapomorphine ([H-3]NPA), to rat striatal membranes in a concentration-dependent manner, with a K(i) of 5 x 10(-7) M. Saturation curves for [H-3]NPA binding in the presence of increasing concentrations of ACTH-(1-24) were performed. Scatchard analysis in the presence of ACTH-(1-24) revealed an increased dissociation constant (K(d)), while the binding capacity (B(max)) was not affected by the peptide, suggesting an apparent competitive interaction between ACTH-(1-24) and [H-3]NPA. ACTH-(1-24) also reduced the binding of the dopamine D2 receptor antagonist [H-3]spiperone to striatal membranes, with a K(i) of 10(-6) M. Much higher concentrations of ACTH-(1-24), up to 10(-4) M, were needed for the displacement of appropriate radiolabelled ligands from dopamine D1 receptors, serotonin 5-HT1A, serotonin 5-HT1B, muscarinic M1 acetylcholine and histamine H-1 receptors. ACTH-(1-24) also inhibited the binding of [H-3]spiperone to dopamine D2 receptors in membranes of the pituitary gland, the septum and the substantia nigra. ACTH-(1-39) and most ACTH fragments and analogs were less potent than ACTH-(1-24) in displacing [H-3]NPA from the dopamine D2 receptor in striatal membranes. In general there was a relationship between displacing potency and chain length. ACTH-(7-16)-NH2 and benzyloxycarbonyl-ACTH-(8-16)-NH2, however, were more potent than ACTH-(1-24) in reducing the binding of [H-3]NPA to dopamine D2 receptors. ACTH-(7-16)-NH2 appeared to contain the minimal required amino acid sequence for inhibition of [H-3]NPA binding, because a further shortening of the peptide resulted in a marked decrease of inhibitory potency. The present data show that ACTH/MSH-like peptides preferentially interact with dopamine D2 receptors.