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Titolo:
Discovery of novel peptidic dopamine transporter ligands by screening a positional scanning combinatorial hexapeptide library
Autore:
Rothman, RB; Baumann, MH; Dersch, CM; Appel, J; Houghten, RA;
Indirizzi:
NIDA, CPS, DIR, NIH, Baltimore, MD 21224 USA NIDA Baltimore MD USA 21224NIDA, CPS, DIR, NIH, Baltimore, MD 21224 USA Torrey Pines Inst Mol Studies, San Diego, CA USA Torrey Pines Inst Mol Studies San Diego CA USA tudies, San Diego, CA USA
Titolo Testata:
SYNAPSE
fascicolo: 3, volume: 33, anno: 1999,
pagine: 239 - 246
SICI:
0887-4476(19990901)33:3<239:DONPDT>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
BIOGENIC-AMINE TRANSPORTERS; POTENTIAL COCAINE ANTAGONISTS; NONHUMAN-PRIMATES; SCHIZOPHRENIC-PATIENTS; SEROTONIN-TRANSPORTER; BINDING-SITES; I-125 RTI-55; DRUGS; IDENTIFICATION; CAUDATE;
Keywords:
transporters; dopamine; serotonin; combinatorial chemistry; cocaine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Rothman, RB NIDA, CPS, DIR, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224USA NIDA 5500 Nathan Shock Dr Baltimore MD USA 21224 MD 21224 USA
Citazione:
R.B. Rothman et al., "Discovery of novel peptidic dopamine transporter ligands by screening a positional scanning combinatorial hexapeptide library", SYNAPSE, 33(3), 1999, pp. 239-246

Abstract

The acute reinforcing effects of cocaine are thought by some to result from cocaine binding to the dopamine (DA) transporter, which inhibits DA uptake and increases synaptic DA levels in the mesolimbic system. Other data suggest that neurotransmitters other than DA contribute to cocaine reinforcement and addiction. These considerations illustrate the need to have additional research tools with which to test the "DA hypothesis. " One strategy is to identify drugs which bind to the DA transporter (DAT ligands) but which do not inhibit DA uptake as effectively as cocaine. The purpose of the present study was to identify members of a novel structural class of DAT ligandsand to characterize their interactions at the DA transporter. A positionalscanning hexapeptide D-amino acid library was screened for inhibition of [I-125]RTI-55 binding to rat caudate DA transporters. Based on the results, 12 peptides were synthesized. All 12 peptides inhibited [I-125]RTI-55 binding to DA transporters with IC50 values, which ranged from 1.8 mu M to 12 muM The two most potent peptides (TPI-669-1 and TPI-669-4) were prepared in larger quantities and were characterized further for activity at the DAT and 5-HT transporter. Both peptides inhibited DA and 5-HT uptake and transporter binding with IC50/K-i values in the low micromolar range. In vivo microdialysis studies demonstrated that both peptides increase extracellular DA and 5-HT in the nucleus accumbens of rats. These data demonstrate that peptides can function as inhibitors of biogenic amine transport. Future work will focus on developing more potent and selective peptides. Published 1999 Wiley-Liss, Inc.dagger.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 10/07/20 alle ore 09:39:19