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Titolo:
Molecular modeling, structure-activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors
Autore:
Wang, SM; Sakamuri, S; Enyedy, IJ; Kozikowski, AP; Zaman, WA; Johnson, KM;
Indirizzi:
Georgetown Univ, Med Ctr, Dept Oncol & Neurosci, Washington, DC 20007 USA Georgetown Univ Washington DC USA 20007 eurosci, Washington, DC 20007 USA Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, Washington,DC 20007 USA Georgetown Univ Washington DC USA 20007 Program, Washington,DC 20007 USA Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA Univ Texas Galveston TX USA 77555 acol & Toxicol, Galveston, TX 77555 USA
Titolo Testata:
BIOORGANIC & MEDICINAL CHEMISTRY
fascicolo: 7, volume: 9, anno: 2001,
pagine: 1753 - 1764
SICI:
0968-0896(200107)9:7<1753:MMSRAF>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
POTENTIAL COCAINE ANTAGONISTS; PIPERIDINE-BASED ANALOGS; REUPTAKE INHIBITORS; HIGH-AFFINITY; 1-<2-ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES GBR-12935; BINDING-SITE; SEROTONIN; ESTER; 1-<2-(DIPHENYLMETHOXY)ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES; PHARMACOLOGY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Wang, SM Georgetown Univ, Med Ctr, Dept Oncol & Neurosci, Bldg D,Room 235-237,4000 Reservoir Rd, Washington, DC 20007 USA Georgetown Univ Bldg D,Room235-237,4000 Reservoir Rd Washington DC USA 20007
Citazione:
S.M. Wang et al., "Molecular modeling, structure-activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors", BIO MED CH, 9(7), 2001, pp. 1753-1764

Abstract

We previously disclosed the discovery of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidul 4-methylphenyl ketone (3) as a novel class of dopamine transporter (DAT) inhibitors and showed that (+/-)-3 has a significant functional antagonism against cocaine in vitro. Our previous preliminary structureactivity relationship study led to identification of a more potent DAT inhibitor [(+/-)-4] but this compound failed to show any significant functional antagonism To search for more potent analogues than 3 but still displaying significant functional antagonism, further SARs, molecular modeling studies and in vitro pharmacological evaluation of this novel class of DAT inhibitors were performed. Sixteen new analogues were synthesized in racemic form and evaluated as DAT inhibitors. It was found that seven new analogues are reasonably potent DAT inhibitors with K-i values of 0.041-0.30 and 0.052-0.16 muM in [H-3]mazindol binding and inhibition of DA reuptake. Chiral isomers of several potent DAT inhibitors were obtained through chiral HPLC separation and evaluated as inhibitors at all the three monoamine transporter sites. In general, the (-)-isomer is more active than the (+)-isomer in inhibition of DA reuptake and all the (-)-isomers are selective inhibitors at the DAT site. Evaluation of cocaine's effect on dopamine uptake in the presence and absence of (+)-3 and (-)-3 showed that (-)-3 is responsible For the functional antagonism obtained with the original lead (+/-)-3. Out of thenew compounds synthesized, analogue (+/-)-20, which is 8- and 3-fold more potent than (+/-)-3 in binding and inhibition of DA reuptake. appeared to hare improved functional antagonism as compared to (+/-)-3. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 19:31:22