title: Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.
abstract: A variety of dicarboxylic acid linkers introduced between the alpha-amino group of Pro(6) and the -amino group of Lys(10) of the cyclic lactam alpha-melanocyte-stimulating hormone (alpha-MSH)-derived Pro(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro(6) residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2')-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a beta-turn-like structure with the D-Phe/D-Nal(2') residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH 2)2-CO-Nle-D-Nal(2')-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic gamma-melanocyte-stimulating hormone (gamma-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.
authors: Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
authors: Alexander V
authors: AV
authors: Mayorov
authors: Minying
authors: M
authors: Cai
authors: Erin S
authors: ES
authors: Palmer
authors: Matthew M
authors: MM
authors: Dedek
authors: James P
authors: JP
authors: Cain
authors: April R
authors: AR
authors: Van Scoy
authors: Bahar
authors: B
authors: Tan
authors: Josef
authors: J
authors: Vagner
authors: Dev
authors: D
authors: Trivedi
authors: Victor J
authors: VJ
authors: Hruby
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D007769:Lactams; C505392:MC3R protein, human; D010456:Peptides, Cyclic; D044104:Receptor, Melanocortin, Type 3; D000521:alpha-MSH; D000242:Cyclic AMP