title: Design, synthesis, and biological evaluation of non-peptidic ligands at the Xenopus laevis skin-melanocortin receptor.
abstract: Taking the tripeptide D-Trp-Arg-Leu-NH(2) as a lead for a Xenopus laevis skin-melanocortin (MC) receptor antagonist, thirteen non-peptidic compounds were synthesized and biologically evaluated at Xenopus laevis melanophores. Six competitive antagonists (shown by Schild analysis) and one partial agonist were identified with moderate activity (IC(50): 5-10 microM). Tryptophanamides with aliphatic side chains were inactive whereas basic residues restored activity. Introducing an imidazole residue yielded partial agonist activity (EC50: 32 microM). Interestingly, constraining the inactive S-tryptophan-isoamylamide to a beta-carboline ring yielded an MC receptor antagonist (42). The specificity for MC receptors was tested at various G-protein coupled receptors. In conclusion, the synthesis of non-peptidic MC receptor antagonists is described which may serve as lead compounds for further studies.
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Tammler
authors.forename: J Mark
authors.initials: JM
authors.lastname: Quillan
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadée
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D002243:Carbolines / Q000737:chemistry; D000242:Cyclic AMP / Q000494:pharmacology; D015195:Drug Design; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008547:Melanophores / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044101:Receptors, Melanocortin; D012867:Skin / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry; D014982:Xenopus laevis; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D000577:Amides; D002243:Carbolines; D007211:Indoles; D008024:Ligands; D009842:Oligopeptides; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D000521:alpha-MSH; D014364:Tryptophan; D000242:Cyclic AMP