title: Further pharmacological characterization of the selective melanocortin 4 receptor antagonist HS014: comparison with SHU9119.
abstract: SHU9119 and HS014 are cyclic MSH analogues which are widely used to elucidate the physiology behind the various effects of the MSH peptides and their receptors. We carefully compared the potency of SHU9119 and HS014 in cells expressing the MC receptor clones. We found that both the peptides are partial agonists for the MC1 and MC5 receptors while they are potent antagonists for the MC3 and MC4 receptors. In agreement with earlier binding data, we found that SHU9119 has equal potency for the MC3 and MC4 receptor whereas HS014 has at least 10-fold higher potency for the MC4 receptor than the MC3 receptor in cAMP assay. Moreover, we synthesized analogues of HS014 where the C-terminal was truncated. We found that this C-terminal fragment of HS014, in particular the Lys(14), has a major influence on the affinity for the MC4 receptor without any particular influence on the affinity for the other MC receptors.
authors.affiliation: Department of Pharmaceutical Pharmacology, Uppsala University, Uppsala, Sweden. helgis@bmc.uu.se
authors.forename: H B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: R
authors.initials: R
authors.lastname: Muceniece
authors.forename: F
authors.initials: F
authors.lastname: Mutulis
authors.forename: A A
authors.initials: AA
authors.lastname: Bouifrouri
authors.forename: I
authors.initials: I
authors.lastname: Mutule
authors.forename: J E
authors.initials: JE
authors.lastname: Wikberg
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D019556:COS Cells; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin; D014162:Transfection; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: C116941:HS014 cyclic peptide; D010456:Peptides, Cyclic; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP