50800-56-1Relevant articles and documents
Tricyclic imidazole antagonists of the Neuropeptide S Receptor
Trotter, B. Wesley,Nanda, Kausik K.,Manley, Peter J.,Uebele, Victor N.,Condra, Cindra L.,Gotter, Anthony L.,Menzel, Karsten,Henault, Martin,Stocco, Rino,Renger, John J.,Hartman, George D.,Bilodeau, Mark T.
scheme or table, p. 4704 - 4708 (2010/10/02)
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.
Halogenated mazindol analogs as potential inhibitors of the cocaine binding site at the dopamine transporter
Houlihan, William J.,Boja, John W.,Parrino, Vincent A.,Kopajtic, Theresa A.,Kuhar, Michael J.
, p. 4935 - 4941 (2007/10/03)
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-α]isoindol-6-ol (23; IC50 1.0 nM; 8x mazindol) and 7-(3',4'-dichlorophenyl)-2,3,4,5-tetrahydro-7H- diazepino[2,1-α]isoindol-7-ol (28; IC50 0.26 nM; 32x 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) uptake site of 5-, 250-, and 465-fold, respectively, and displayed weak or no affinity for a variety of neurotransmitter receptor sites.
