title: Effects of macrocycle size and rigidity on melanocortin receptor-1 and -5 selectivity in cyclic lactam alpha-melanocyte-stimulating hormone analogs.
abstract: The effects of the linker arm rigidity and size on melanocortin receptor selectivity were explored in a series of compounds using cyclic lactam alpha-melanocyte-stimulating hormone template. A variety of dicarboxylic acid linkers introduced between the alpha-amino group of His(6) and the epsilon-amino group of Lys(10) lead to high-affinity, selective human melanocortin receptor-1 and -5 (hMC1R and hMC5R) antagonists. The incorporation of hydrophilic functions into the linker arm was found to be unfavorable for both binding potency and receptor selectivity. Analogs 8 and 9 containing highly conformationally constrained hydrophobic linkers (m- and p-phthalic acids) were found to be selective nanomolar range hMC1R antagonists (IC(50) = 7 and 4 nm, respectively), whereas the employment of a small conformationally constrained linker (maleic acid) resulted in a high-affinity (IC(50) = 19 nm) and selective hMC5R antagonist (analog 12). These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-1 and -5 receptors.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mayorov
authors.forename: So-Yeop
authors.initials: SY
authors.lastname: Han
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hammer
authors.forename: Dev
authors.initials: D
authors.lastname: Trivedi
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000737:chemistry; D015394:Molecular Structure; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044101:Receptors, Melanocortin; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047029:Lactams, Macrocyclic; D044102:Receptor, Melanocortin, Type 1; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; D000521:alpha-MSH; D000262:Adenylyl Cyclases