Halogenated mazindol analogs as potential inhibitors of the cocaine binding site at the dopamine transporter

Journal of Medicinal Chemistry
William J HoulihanM J Kuhar

Abstract

A series of halogenated (F, Cl, Br, I), pyrimido and diazepino homologs of mazindol were prepared and evaluated for their ability to displace [3H]WIN 35,428 binding and to inhibit uptake of [3H]dopamine (DA) in rat striatal tissue. All of the compounds except for the 2'-chloro (6) and 2'-bromo (16) analogs of mazindol displaced [3H]WIN 35,428 binding and inhibited [3H]DA uptake more effectively than (R)-cocaine. Structure-activity studies indicated that best inhibition of [3H]WIN 35,428 binding occurred in the imidazo series with compounds containing one or two Cl or Br atoms in the 3'- or 4'-position of the free phenyl group. Replacement of the imidazo ring by a pyrimido or diazepino ring enhanced binding inhibition. The most potent inhibitors of [3H]WIN 35,428 binding and [3H]DA uptake were 6-(3'-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-alpha]isoind ol-6-ol (23; IC50 1.0 nM; 8 x mazindol) and 7-(3',4'-dichlorophenyl)-2,3,4,5-tetrahydro-7H-diazepino[2,1-alpha ]isoindol-7-ol (28; IC50 0.26 nM; 32 x mazindol), respectively. No significant differences was found between binding and uptake inhibition. Mazindol and the pyrimido and diazepino homologs 24 and 27 showed a selectivity for the DA uptake over the serotonin (5-HT) upta...Continue Reading

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Citations

Nov 13, 2003·European Journal of Pharmacology·Aloke K DuttaMaarten E A Reith
May 17, 2005·Pharmacology, Biochemistry, and Behavior·Yasuhiro KawakamiYutaka Gomita
Dec 31, 2002·European Journal of Pharmacology·William J Houlihan, Lawrence Kelly
May 20, 1998·Pharmacology, Biochemistry, and Behavior·M V SolbrigW I Lipkin
Jul 20, 2002·Bioorganic & Medicinal Chemistry Letters·Subramaniam AnanthanRichard B Rothman
Jun 29, 2013·The Journal of Organic Chemistry·Wendy A LoughlinMaria J Petersson
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·I D KuntzP A Kollman
Mar 2, 2021·Medicinal Research Reviews·Yohan MalkiNicolas Masurier

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