title: Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors.
abstract: A novel hybrid melanocortin pharmacophore was designed based on the topographical similarities between the pharmacophores of Agouti related protein (AGRP) an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. When employed in two different 23-membered macrocyclic lactam peptide templates, the designed hybrid AGRP/MSH pharmacophore yielded non-competitive ligands with nanomolar range binding affinities. The topography-based pharmacophore hybridization strategy will prove useful in development of unique non-competitive melanocortin receptor modulators.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mayorov
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Erin S
authors.initials: ES
authors.lastname: Palmer
authors.forename: Dustin K
authors.initials: DK
authors.lastname: Tanaka
authors.forename: James P
authors.initials: JP
authors.lastname: Cain
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Dedek
authors.forename: Bahar
authors.initials: B
authors.lastname: Tan
authors.forename: Dev
authors.initials: D
authors.lastname: Trivedi
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D054369:Agouti-Related Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry*; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D044101:Receptors, Melanocortin / Q000378:metabolism*; D000521:alpha-MSH / Q000737:chemistry / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; D007769:Lactams; D008024:Ligands; D044101:Receptors, Melanocortin; D000521:alpha-MSH