STRUCTURE-ACTIVITY STUDIES OF 6-(TETRAZOLYLALKYL)-SUBSTITUTED DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AMPA RECEPTOR ANTAGONISTS .1. EFFECTSOF STEREOCHEMISTRY, CHAIN-LENGTH, AND CHAIN SUBSTITUTION

A series of 6-substituted decahydroisoquinoline-3-carboxylic acids wer e prepared as excitatory amino acid (EAA) receptor antagonists. These compounds are antagonists at the N-methyl-D-aspartate (NMDA) and amino -3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA) subclasses o f ligand gated ion channel (ionotropic) EAA receptors. ,4a,5,6,7,8,8a- decahydroisoquiinoline-3-carboxylic acid (9) is a potent, selective an d systemically active AMPA antagonist. Other analogs from this series, including 4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (32 ) and 4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (61) are potent, selective, and systemically active NMDA antagonists. This and the subsequent publication look at the AMPA antagonist aspects of thi s SAR. Herein we report the effects of varying stereochemistry around the hydroisoquinoline ring; of tetrahydro- versus decahydroisoquinolin e; of having the carboxylic acid at C-1 versus C-3; of varying the len gth of the carbon chain connecting a tetrazole to the bicyclic nucleus ; and of holding the connecting chain constant at two atoms, the effec t 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 th e binding of radioligands selective for AMPA ([H-3]AMPA), NMDA ([H-3]C GS 19755), and kainic acid ([H-3]- kainic acid) receptors and for thei r ability to inhibit depolarizations induced by AMPA (40 mu M), NMDA ( 40 mu M), and kainic acid (10 mu M). Our findings revealed that the op timal stereochemical array was the same for both NMDA (32 and 61) and AMPA (9) antagonists identified in this series and that the tetrahydro isoquinoline (25) and the C-1 carboxy (30) analogs of 9 are inactive. With a tetrazole in the distal acid position, an ethylene spacer (9) i s optimal; substitution with oxygen or nitrogen on the chain in the po sition adjacent to the bicyclic nucleus significantly reduced activity , while substitution with a methyl or phenyl group on the chain was we ll tolerated.