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ACTH/MSH-like peptides inhibit the binding of dopaminergic ligands to the dopamine D2 receptor in vitro

1991; Elsevier BV; Volume: 207; Issue: 1 Linguagem: Inglês

10.1016/s0922-4106(05)80036-7

1872-8251

Wouter J. Florijn, Wierd Mathijs de Boer, J.A.D.M. Tonnaer, J. W. VAN NISPEN, Dirk H.G. Versteeg,

Stress Responses and Cortisol

ACTH-(1-24) decreased the binding of the dopamine D2 receptor agonist, [3H]N-propylnorapomorphine ([3H]NPA), to rat striatal membranes in a concentration-dependent manner, with a Ki of 5 × 10−7 M. Saturation curves for [3H]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 (Kd), while the binding capacity (Bmax) was not affected by the peptide, suggesting an apparent competitive interaction between ACTH-(1-24) and [3H]NPA. ACTH-(1-24) also reduced the binding of the dopamine D2 receptor antagonist [3H]spiperone to striatal membranes, with a Ki 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 H1 receptors. ACTH-(1-24) also inhibited the binding of [3H]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 [3H]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 [3H]NPA to dopamine D2 receptors. ACTH-(7-16)-NH2 appeared to contain the minimal required amino acid sequence for inhibition of [3H]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.