title: Structure-activity studies of the melanocortin peptides: discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors.
abstract: We have designed and synthesized several novel cyclic SHU9119 analogues (Ac-Nle4-[Asp5-His6-DNal(2')7-Arg8-Trp9-Lys10]-NH2) modified in position 6 with nonconventional amino acids. SHU9119 is a high affinity nonselective antagonist at hMC3R and hMC4R with potent agonist activity at hMC1R and hMC5R. We measured the binding affinity and agonist potency of the novel analogues at cloned hMC3R, hMC4R, and hMC5R receptors and identified several selective, high affinity hMC3R and hMC4R antagonists. Compound 4 containing Che substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.48 nM) with 100-fold selectivity over hMC3R antagonist. Analogue 7 with a Cpe substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.51 nM) with a 200-fold selectivity vs the hMC3R. Interestingly, analogue 9 with an Acpc residue in position 6 is a high affinity hMC3R antagonist (IC50 = 2.5 nM) with 100-fold selectivity vs the hMC4R antagonist based on its binding affinities. This compound represents the first cyclic lactam antagonist with high selectivity for the hMC3R vs hMC4R. To understand the possible structural basis responsible for selectivity of these peptides at hMCR3 and hMCR4, we have carried out a molecular modeling study in order to examine the conformational properties of the cyclic peptides modified in position 6 with conformationally restricted amino acids.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Devendra
authors.initials: D
authors.lastname: Trivedi
authors.forename: David
authors.initials: D
authors.lastname: Weinberg
authors.forename: Tanya
authors.initials: T
authors.lastname: MacNeil
authors.forename: L H T
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors*; D044101:Receptors, Melanocortin; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008024:Ligands; C470072:MC4R protein, human; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C469562:acetyl-norleucyl-cyclo(aspartyl-Aic-(2-naphthyl)alanyl-arginyl-tryptophyl-lysyl)amide; C469563:acetyl-norleucyl-cyclo(aspartyl-cyclopentyl-(2-naphthyl)alanyl-arginyl-tryptophyl-lysyl)amide; C086971:melanocortin 5 receptor; D000521:alpha-MSH; D000242:Cyclic AMP