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Titolo:
TOPOGRAPHICAL MODIFICATION OF MELANOTROPIN PEPTIDE ANALOGS WITH BETA-METHYLTRYPTOPHAN ISOMERS AT POSITION-9 LEADS TO DIFFERENTIAL POTENCIESAND PROLONGED BIOLOGICAL-ACTIVITIES
Autore:
HASKELLLUEVANO C; BOTEJU LW; MIWA H; DICKINSON C; GANTZ I; YAMADA T; HADLEY ME; HRUBY VJ;
Indirizzi:
UNIV ARIZONA,DEPT CHEM TUCSON AZ 85721 UNIV ARIZONA,DEPT CHEM TUCSON AZ 85721 UNIV ARIZONA,DEPT ANAT TUCSON AZ 85721 UNIV MICHIGAN,MED CTR,DEPT INTERNAL MED ANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT PEDIAT ANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT SURG ANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT PHYSIOL ANN ARBOR MI 48109
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 23, volume: 38, anno: 1995,
pagine: 4720 - 4729
SICI:
0022-2623(1995)38:23<4720:TMOMPA>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
MELANOCYTE-STIMULATING HORMONE; ALPHA-MELANOTROPIN; PRO-OPIOCORTIN; DESIGN; SUPERPOTENT; RECEPTORS; CONFORMATION; SEQUENCE; CLONING; INVITRO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
56
Recensione:
Indirizzi per estratti:
Citazione:
C. Haskellluevano et al., "TOPOGRAPHICAL MODIFICATION OF MELANOTROPIN PEPTIDE ANALOGS WITH BETA-METHYLTRYPTOPHAN ISOMERS AT POSITION-9 LEADS TO DIFFERENTIAL POTENCIESAND PROLONGED BIOLOGICAL-ACTIVITIES", Journal of medicinal chemistry, 38(23), 1995, pp. 4720-4729

Abstract

We have introduced topographical constraints at the 9 position of a superpotent cyclic alpha-melanotropin analogue, )-Asp(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys(10)-NH2, by incorporating a methyl group at the beta-carbon of Trp(9). These studies were performed on the Trp side chainpharmacophore to identify the bioactive topography of the indole moiety with melanocortin MC1 receptors. The four beta-MeTrp(9) isomers, inaddition to the stereochemical controls L- and DTrp(9), were used to probe differential receptor molecular recognition of the tryptophan moiety in two bioassay systems. Approximately a 460-fold difference in potency was observed between the diastereoisomeric peptides in the frogskin bioassay, with only 33- and 10-fold efficacy differences observed in binding and intracellular cAMP accumulation, respectively, on thehuman melanocortin receptor, hMC1R. The relative orders of potencies in the frog skin bioassay were 2R,3S > 2S,3S = 2R,3R >> 2S,3R and for the hMC1R were 2S,3S > 2R,3R > 2R,3S >> 2S,3R. Of particular interest is the ability of these topographically constrained ligands to differentially affect prolonged biological activity. The 2R,3R diastereoisomeric peptide possessed superprolonged activity, whereas the 2S,3S peptide lacked any residual activity in the frog skin bioassay. However, onthe melanocortin receptor, the 2S,3S diastereoisomeric peptide maintained slow dissociation rates (t(1/2) = 7 h), while the other diastereoisomeric peptides possessed dissociation t(1/2) rates of ca. 2 h. These data strongly implicate ligand-receptor interactions and kinetics ascontributing to the observed prolonged biological activities and clearly illustrate topographical recognition differences between these twoperipheral MC1 receptors involved in skin pigmentation. This study also demonstrates that topographical modifications of pharmacophore sidechain residues, in addition to identifying preferential side chain orientation, can be a useful strategy for the design of peptides to increase the duration of biological activity, relative to the native ligand.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/09/20 alle ore 01:06:29