title: Fmoc-based solid-phase synthesis of GPR54-agonistic pentapeptide derivatives containing alkene- and fluoroalkene-dipeptide isosteres.
abstract: Fmoc-protected Phe-Gly-type (Z)-alkene dipeptide isostere (ADI) and (E)-fluoroalkene dipeptide isostere (FADI) were synthesized and applied to Fmoc-based solid-phase peptide synthesis (SPPS). These cis-peptide bond mimetics were introduced into a bioactive pentapeptide [H-Amb-Phe-Gly-Leu-Arg-Trp-NH(2); Amb = 4-(aminomethyl) benzoic acid], which has potent GPR54 agonistic activity. The resulting pentapeptide derivatives showed low GPR54 agonistic activity, as compared with the parent peptide and (E)-ADI-containing derivative. This suggests that the trans-amide conformer of Phe-Gly peptide bond of the parent peptide would be significantly important for bioactivity. Contrary to our expectations, a (Z)-FADI-containing derivative exhibited essentially no activity, revealing the necessity of critical validation of FADI-bioisosterism.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomita
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Narumi
authors.forename: Ayumu
authors.initials: A
authors.lastname: Niida
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000596:Amino Acids; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005449:Fluorenes; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000074502:Receptors, Kisspeptin-1
chemical_list: D000475:Alkenes; D000596:Amino Acids; D004151:Dipeptides; D005449:Fluorenes; C118688:KISS1R protein, human; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1