ACTH/MSH-like peptides inhibit the binding of dopaminergic ligands to the dopamine D2 receptor in vitro.
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 x 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Rudolf Magnus Institute, Department of Pharmacology, Medical Faculty, University of Utrecht, The Netherlands.
W J
WJ
Florijn
T
T
De Boer
J A
JA
Tonnaer
J W
JW
Van Nispen
D H
DH
Versteeg
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives; D003366:Cosyntropin / Q000494:pharmacology; D015259:Dopamine Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism
D015259:Dopamine Agents; D008024:Ligands; D010446:Peptide Fragments; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D003366:Cosyntropin; D013134:Spiperone; C009074:N-n-propylnorapomorphine; D011813:Quinuclidinyl Benzilate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones; D001058:Apomorphine