178375-00-3Relevant articles and documents
COMBINATIONS FOR THE TREATMENT OF PARKINSONISM CONTAINING SELECTIVE NMDA ANTAGONISTS
-
, (2008/06/13)
This invention relates to a method of treating Parkinson's Disease whereby a mammal suffering from Parkinson's Disease is treated with a combination of a forebrain selective NMDA antagonist and a compound which is capable of increasing the excitatory feedback from the ventral lateral nucleus of the thalamus into the cortex. This invention also relates to pharmaceutical compositions containing the synergistic combination.
(3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: A conformationally restricted analogue of the NRr2B subtype-selective NMDA antagonist (1S,2S)-1-(4-hydroxyphenyl)-2(4-hydroxy-4-phenylpiperidino)-1- propanol
Butler, Todd W.,Blake, James F.,Bordner, Jon,Butler, Paul,Chenard, Bertrand L.,Collins, Mary A.,DeCosta, Debra,Ducat, Mary J.,Eisenhard, Michael E.,Menniti, Frank S.,Pagnozzi, Martin J.,Sands, Steven B.,Segelstein, Barbara E.,Volberg, Walter,White, W. Frost,Zhao, Dayao
, p. 1172 - 1184 (2007/10/03)
(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1)is a recently described antagonist of N-methyl-D-aspartate (NUDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NUDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptor - cis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)- 3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol (12a, CP- 283,097), was found to possess potency and selectivity comparable to CP- 101,606. Thus 12a is a new tool to explore the function of the NR2B- containing NUDA receptors.