A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.

Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.

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1985.CGS 9895 is a pyrazoloquinoline closely related to the benzodiazepine agonist CGS 9896 and the benzodiazepine antagonist CGS 8216. In anxiolytic test procedures, this compound generalizes to CGS 9896 discriminative stimuli, produces an increase in punished responding, and partially antagonizes pentylenetetrazol discriminative stimuli. This anxiolytic activity is not, however, accompanied by any detectable sedation or muscle relaxation. CGS 9895 does not impair rotorod performance or reduce motor activity and does not potentiate ethanol-induced rotorod impairment or hexobarbital-induced sleeptime. This compound does not generalize to diazepam discriminative stimuli, suggesting a difference between the internal stimuli produced by this drug and those of diazepam. Only weak anticonvulsant activity is noted with CGS 9895. In addition to the benzodiazepine agonist effects of this compound, CGS 9895 is capable of antagonizing the rotorod deficit produced by diazepam. It also selectively antagonizes the sedative effect of diazepam in the conflict procedure without reducing the anxiolytic effect of diazepam. Overall, CGS 9895 exhibits a novel combination of benzodiazepine agonist and antagonist properties. This unique profile suggests that CGS 9895 may be a clinically useful, novel anxiolytic agent.

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