title: N-methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity.
abstract: A series of singularly N-methylated analogs of Ac[Nle28,31]CCK(26-33) were synthesized by the solid-phase methodology, and their biological activity was tested in three different in vitro bioassays. The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-methyl analogs were agonists in all three bioassays. N-Methylation at either N- or C-terminals did not affect potency and selectivity, whereas N-methylation of internal residues [Nle28,(N-Me)Nle31]- and [Nle28,31,(N-Me)Trp30]CCK(26-33) in the sequence resulted in analogs which were 10-fold less potent than Ac[Nle28,31]CCK(26-33) in all three preparations. Different rank orders of potencies observed for [Nle28,31,Sar29]- and [Nle28,31,(N-Me)Asp32]CCK(26-33) analogs correspond to increased selectivity to either GPGB or GPS, respectively. We propose that systematic N-methylation of single amide bonds in a bioactive peptide should be conducted as an additional routine to probe structure-activity relationships.
authors.affiliation: Department of Pharmaceutical Chemistry, Hadassah-University Hospital, Jerusalem, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Ron
authors.forename: C
authors.initials: C
authors.lastname: Gilon
authors.forename: M
authors.initials: M
authors.lastname: Hanani
authors.forename: A
authors.initials: A
authors.lastname: Vromen
authors.forename: Z
authors.initials: Z
authors.lastname: Selinger
authors.forename: M
authors.initials: M
authors.lastname: Chorev
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005704:Gallbladder / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; C050553:cholecystokinin (26-33), N-acetyl-norleucine(28,31)-; D012844:Sincalide