Structure−Activity Studies of 6-(Tetrazolylalkyl)-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. 1. Effects of Stereochemistry, Chain Length, and Chain Substitution

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.

Drugs in the tetrazole series. (Review)

“…One such preparation 5 was discovered after a study of a series of 6-substituted decahydroisoquinoline-3-carboxylic acids [17]. Study of the biological activity showed that preparation 5 is an effective mixed antagonist of AMPA -2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid and kainate receptors and at the same time has lower neurotoxicity than known antagonists of AMPA and NMDA (N-methyl-D-aspartic acid) receptors.…”

GluK1 inhibits calcium dependent and independent transmitter release at associational/commissural synapses in area CA3 of the hippocampus

“…We therefore applied the GluK1 specific agonist (S)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isothiazolyl)propionic acid (ATPA) (Ornstein et al, 1996, Clarke et al, 1997Clarke and Collingridge, 2002;Clarke and Collingridge, 2004) to investigate the influence of this receptor in AMPAR mediated synaptic transmission at A/C synapses. Application of 1 lM ATPA for 5 min induced a synaptic depression which was reversed by wash-out of the drug.…”

GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

“…The initial compounds displayed high, although nonselective, affinity for AMPA and NMDA receptors, but through extensive SAR studies, highly potent and selective compounds such as RPR 119990 (159) and RPR 117824 (160) have been identified. At least two classes of amino-acid-containing compounds, based on decahydroisoquinoline-3-carboxylic acid [362] and AMPA [363], have been found to be competitive AMPA receptor antagonists. At least two classes of amino-acid-containing compounds, based on decahydroisoquinoline-3-carboxylic acid [362] and AMPA [363], have been found to be competitive AMPA receptor antagonists.…”