Paul Ornstein - Structure-activity studies of 6-(tetrazolylalkyl)-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 1. Effects of stereochemistry, chain length, and chain substitution.

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  Ornstein, P L, Arnold, M B, Allen, N K, Bleisch, T, Borromeo, P   S, Lugar, C W, Leander, J D, Lodge, D, Schoepp, D D Journal   Of Medicinal Chemistry 1996 39  (11) 2219-2231

  Abstract: A series of 6-substituted   decahydroisoquinoline-3-carboxylic acids were prepared as   excitatory amino acid (EAA) receptor antagonists. These compounds   are antagonists at the N-methyl-D-aspartate (NMDA) and   2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl) propanoic acid (AMPA)   subclasses of ligand gated ion channel (ionotropic) EAA   receptors. (3S,4aR, 6R,8aR)-6-(2-(1H-tetrazol-5-yl)ethyl)-   1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (9)   is a potent, selective and systemically active AMPA antagonist.   Other analogs from this series, including   (3S,4aR,6S,8aR)-6-((1H-tetrazol-5-yl)methyl)-   1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid   (32) and (3S,4aR,6S,8aR)-6-   (phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-ca   rboxylic acid (61) are potent, selective, and systemically active   NMDA antagonists. This and the subsequent publication look at the   AMPA antagonist aspects of this SAR. Herein we report the effects   of varying stereochemistry around the hydroisoquinoline ring; of   tetrahydro-versus decahydroisoquinoline; of having the carboxylic   acid at C-1 versus C-3; of varying the length of the carbon chain   connecting a tetrazole to the bicyclic nucleus; and of holding   the connecting chain constant at two atoms, the effect of   heteroatom substitution in the position adjacent to the bicyclic   nucleus and substitution with methyl or phenyl on the chain.   Compounds were evaluated on rat cortical tissue for their ability   to inhibit the binding of radioligands selective for AMPA   ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]-kainic   acid) receptors and for their ability to inhibit depolarizations   induced by AMPA (40 microM), NMDA (40 microM), and kainic acid   (10 microM). Our findings revealed that the optimal   stereochemical array was the same for both NMDA (32 and 61) and   AMPA (9) antagonists identified in this series and that the   tetrahydroisoquinoline (25) and the C-1 carboxy (30) analogs of 9   are inactive. With a tetrazole in the distal acid position, an   ethylene spacer (9) is optimal; substitution with oxygen or   nitrogen on the chain in the position adjacent to the bicyclic   nucleus significantly reduced activity, while substitution with a   methyl or phenyl group on the chain was well tolerated.;

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