title: Design and synthesis of a library of tertiary amides: evaluation as mimetics of the melanocortins' active core.
abstract: Two hundred and ten tertiary amides were prepared on solid phase. Diamines were coupled to activated carboxylated Wang polymer, and the polymeric substituted benzyloxycarbonyl protected diamines obtained were reacted with aldehydes or ketones in trimethyl orthoformate giving resin attached Schiff bases. Coupled resins were then reduced to secondary amines by sodium cyanoborohydride in 4% acetic acid/trimethyl orthoformate, followed by acylation with the carboxylic acid in the presence of PyBroP and diisopropylethylamine. Cleavage of tertiary amides from the resin was made by trifluoroacetic acid in the presence of scavengers (mainly 1,2-ethanedithiol). When indole derivatives were prepared, parallel alkylation with the linker fragment occurred, giving derivatives of 2-(4-hydroxybenzyl)-indole as side products. Solution synthesis or mixed liquid/solid phase preparation of title substances proved to be advantageous in cases when the above method did not give acceptable results. According to this approach an efficient formation of Schiff bases was achieved in the presence of TiCl(4). Substances were isolated by reversed phase chromatography; in some cases isomers were additionally separated by chiral chromatography on Chirobiotic T. When tested on human recombinant melanocortin receptors all the tertiary amides showed some binding affinities; for the highest affinity compounds the K(i)s reached 400 nM on MC(1), 2 microM on MC(3) and 1 microM on MC(4) and MC(5) receptors. cAMP assays of some of the title compounds showed that the tertiary amides are melanocortin receptor antagonists on the four MC receptor subtypes.
authors.affiliation: Department of Pharmaceutical Biosciences, Division of Pharmacology, Uppsala Biomedical center, Uppsala University, Uppsala, Sweden.
authors.forename: Felikss
authors.initials: F
authors.lastname: Mutulis
authors.forename: Jana
authors.initials: J
authors.lastname: Kreicberga
authors.forename: Sviatlana
authors.initials: S
authors.lastname: Yahorava
authors.forename: Ilze
authors.initials: I
authors.lastname: Mutule
authors.forename: Larisa
authors.initials: L
authors.lastname: Borisova-Jan
authors.forename: Aleh
authors.initials: A
authors.lastname: Yahorau
authors.forename: Ruta
authors.initials: R
authors.lastname: Muceniece
authors.forename: Sandra
authors.initials: S
authors.lastname: Azena
authors.forename: Santa
authors.initials: S
authors.lastname: Veiksina
authors.forename: Ramona
authors.initials: R
authors.lastname: Petrovska
authors.forename: Jarl E S
authors.initials: JE
authors.lastname: Wikberg
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D032701:Biomimetics; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D053486:Melanocortins / Q000737:chemistry* / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D018716:Molecular Mimicry; D015394:Molecular Structure; D012996:Solutions; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D000577:Amides; D053486:Melanocortins; D012996:Solutions; D000521:alpha-MSH; D000242:Cyclic AMP