Incorporation of vinylogous scaffolds in the C-terminal tripeptide of substance P.
Glycine-9 and leucine-10 of substance P (SP) are critical for (NK)-1 receptor recognition and agonist activity. Propsi(Z)-CH=CH(CH3)-CONH)Leu (or Met) and Propsi((E)-CH=CH(CH3)-CONH)Leu (or Met) have been introduced in the sequence of SP, in order to restrict the conformational flexibility of the C-terminal tripeptide, Gly-Leu-Met-NH2, of SP. Propsi((Z)-CH=C(CH2CH(CH3)2)-CONH)Met-NH2, with an isobutyl substituent to mimic the Leu side-chain, was also incorporated in place of the C-terminal tripeptide. The substituted-SP analogs were tested for their affinity to human NK-1 receptor specific binding sites (NK-1M and NK-1m) and their potency to stimulate adenylate cyclase and phospholipase C in Chinese Hamster ovary (CHO) cells transfected with the human NK-1 receptor. The most potent SP analogs [Pro9psi((Z)CH=C(CH3)CONH)Leu10]SP and [Pro9psi ((E)CH=C(CH3)CONH)Leu10]SP, are about 100-fold less potent than SP on both binding sites and second messenger pathways. These vinylogous (Z)- or (E)-CH=C(CH3)- or (Z)-CH=C(CH2CH(CH3)2) moieties hamper the correct positioning of the C-terminal tripeptide of SP within both the NK-1M- and NK-1m-specific binding sites. The origin of these lower potencies is related either to an incorrect peptidic backbone conformation and/or an unfavorable receptor interaction of the methyl or isobutyl group.
Laboratoire de Chimie Organique Biomoléculaire, Institut Nancéien de Chimie Moléculaire, Université H. Poincaré, Vandoeuvre-les-Nancy Cedex, France.
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D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002918:Chymotrypsin / Q000737:chemistry; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018040:Receptors, Neurokinin-1 / Q000737:chemistry; D015398:Signal Transduction; D013373:Substance P / Q000737:chemistry*; D014162:Transfection
D010455:Peptides; D018040:Receptors, Neurokinin-1; D013373:Substance P; D000242:Cyclic AMP; D002918:Chymotrypsin; D005998:Glycine