Structure−Activity Studies of 6-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. 2. Effects of Distal Acid Bioisosteric Substitution, Absolute Stereochemical Preferences, and in Vivo Activity

• Published in: Journal of medicinal chemistry Vol. 39; no. 11; pp. 2232 - 2244
• Main Authors: Ornstein, Paul L, Arnold, M. Brian, Allen, Nancy K, Bleisch, Thomas, Borromeo, Peter S, Lugar, Charles W, Leander, J. David, Lodge, David, Schoepp, Darryle D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.05.1996; Amer Chemical Soc
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; Animals; Biological and medical sciences; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cerebral Cortex - metabolism; Chemistry, Medicinal; Electroshock; Glutamatergic system (aspartate and other excitatory aminoacids); Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Kainic Acid - metabolism; Life Sciences & Biomedicine; Medical sciences; Mice; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pipecolic Acids - metabolism; Rats; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - metabolism; Science & Technology; Seizures - prevention & control; Stereoisomerism; Structure-Activity Relationship; PHENCYCLIDINE-LIKE DRUGS; BINDING; BRAIN; METHYL-D-ASPARTATE; Tetrazole derivatives; Intraperitoneal administration; Enantioselectivity; Isoxazole derivatives; Rat; Nitrogen heterocycle; Central nervous system; Phosphonic acids; Glutamate receptor; Structure activity relation; Bicyclic compound; Antagonist; Neurological disorder; Chemical synthesis; Rodentia; In vitro; Sulfonic acid; In vivo; Vertebrata; Chemotherapy; Experimental disease; AMPA receptor; Mammalia; Treatment; Convulsion; Mouse; Animal; Excitatory aminoacid; Triazole derivatives; NMDA receptor; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950913h

We have explored the excitatory amino acid antagonist activity in a series of decahydroisoquinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl)ethyl)decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure−activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic, phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in 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 μM), NMDA (40 μM), and kainic acid (10 μM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.