Identification of antagonists for melanocortin MC3, MC4 and MC5 receptors.
Antagonists for the melanocortin receptor family were identified by analysis of the effects of four melanocortin analogues on alpha-MSH(alpha-melanocyte-stimulating hormone)-induced cAMP accumulation in 293 human embryonal kidney (HEK) cells that expressed either the rat melanocortin MC3 receptor, the human melanocortin MC4 receptor or the ovine melanocortin MC5 receptor. Two peptides, [D-Arg8]ACTH(adrenocorticotrope hormone)-(4-10) and [Pro8,10,Gly9]ACTH-(4-10), antagonized the action of alpha-MSH on the melanocortin MC4 and MC5 receptors, but not the melanocortin MC3 receptor. [Ala6]ACTH-(4-10) inhibited the alpha-MSH activation of the melanocortin MC3 and MC5, but only weakly antagonized the activation of the melanocortin MC4 receptor. [Phe-I7]ACTH-(4-10) antagonized the melanocortin MC3, MC4 and MC5 receptors equally well. These antagonists were also tested to block a behavioral response induced by alpha-MSH. alpha-MSH-induced excessive grooming behavior in rats was inhibited by [Phe-I7]ACTH-(4-10), [D-Arg8]ACTH-(4-10) and [Pro8,10,Gly9]ACTH-(4-10), but not by [Ala6]ACTH-(4-10). This suggests that alpha-MSH-induced excessive grooming behavior is mediated by melanocortin MC4 receptors.
Adan
R A
RA
Department of Medical Pharmacology, Utrecht University, Netherlands.
Oosterom
J
J
Ludvigsdottir
G
G
Brakkee
J H
JH
Burbach
J P
JP
Gispen
W H
WH
D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006120:Grooming / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors*; D044101:Receptors, Melanocortin; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors*; D012756:Sheep; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D018000:Receptors, Peptide; C086971:melanocortin 5 receptor; C034159:ACTH (4-10), Phe(7)-; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP; C011394:ACTH (4-10)