title: Potent and selective peptide agonists of alpha-melanocyte stimulating hormone (alphaMSH) action at human melanocortin receptor 5; their synthesis and biological evaluation in vitro.
abstract: Melanocortin receptors (MC1-5R) and their endogenous ligands (melanocyte-stimulating hormones and adrenocorticotropic hormone) are involved in many physiological processes in humans. Of those receptors, the actions of MC5R are the least understood despite its broad presence in the numerous peripheral tissues and brain. In this study, we describe synthesis and pharmacological properties in vitro (receptor-binding affinity and agonist activity) of several cyclic analogs of alphaMSH which are potent agonists at hMC5R (EC(50) below 1 nM) and of enhanced receptor subtype selectivity (more than 2000-fold versus hMC1b,3R and about 70- to 200-fold versus hMC4R). These compounds are analogs of Ac-Nle(4)-cyclo[Asp(5)-His(6)-D-Nal(2')(7)-Pip(8)-Trp(9)-Lys(10)]-NH(2) (Pip: pipecolic acid) in which His(6) has been replaced with sterically hindered amino acids. They may be useful tools in the elucidation of the MC5R role in skin disorders and in immunomodulatory and in anti-inflammatory actions of alphaMSH.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ, USA. maria_bednarek@merck.com
authors.forename: Maria A
authors.initials: MA
authors.lastname: Bednarek
authors.forename: Tanya
authors.initials: T
authors.lastname: MacNeil
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: M
authors.initials: M
authors.lastname: Angeles Cabello
authors.forename: Marta
authors.initials: M
authors.lastname: Maroto
authors.forename: Ana
authors.initials: A
authors.lastname: Teran
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D018043:Receptors, Corticotropin / Q000819:agonists*; D044101:Receptors, Melanocortin; D000521:alpha-MSH / Q000819:agonists*
chemical_list: D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; D000521:alpha-MSH