This proposal will investigate the metabolism and pharmacological mode of action of a new class of anticonvulsants with novel chemical structures, the 1,2,3-triazolines, represented by the lead compound ADD17014. The triazolines have recently emerged as a potentially unique family of anticonvulsant agents whose mechanism of action is unknown. On chemical considerations, it is likely that these compounds exert their pharmacological activity by acting as prodrugs that generate the 'active' Alpha-amino acid species in vivo. In this respect, their mode of action would seem to be quite different from the more traditional anticonvulsants. Other data accumulated for ADD17014, including receptor binding studies also suggest a possible involvement of some expression of Alpha-amino acid (inhibitory glycine or excitatory glutamate/aspartate) neurotransmission in their anticonvulsant action. Thus we propose to determine (1) if ADD17014, a triazoline that has advanced through all 7 phases of NIH anticonvulsant testing and which has a profile resembling that of phenobarbital and valproate, undergoes biotransformation into Alpha-amino acid metabolites and (2) if these metabolites do indeed mediate its anticonvulsant action. Thus our objectives are to (a) synthesize 14C-labeled ADD17014 and perform radiolabeled metabolic tracer studies in two animal species: the mouse and the rat. The metabolic profile of ADD17014 over an appropriate time course will be determined and correlated with its in vivo anticonvulsant activity, in both species. Tissue distribution of radiolabel and of drug and metabolites in selected tissues will be performed, as well as blood and urinary metabolic profiles. Metabolite identification and quantitation will be achieved using high-pressure liquid radio-chromatographic analysis utilizing authentic standards of potential metabolites that will be synthesized in our laboratories. (b) To determine the effect of ADD17014 and potential metabolites on various pre and post synaptic markers of inhibitory (GABA/glycine) and excitatory (glutamate/aspartate) amino acid neurotransmission. In vitro measurements of release, uptake, binding and receptor-effector coupling will be conducted. The study will provide valuable data on the metabolism and mode of action of this new class of anticonvulsant drug. They can aid in the more rational design of safer and more effective anticonvulsant agents and provide a rational basis for using these agents as probes to study basic mechanisms of epilepsy.
| Kadaba, P K; Stevenson, P J; P-Nnane, I et al. (1996) Triazolines--XXVII. delta2-1,2,3-triazoline anticonvulsants: novel 'built-in' heterocyclic prodrugs with a unique 'dual-action' mechanism for impairing excitatory amino acid L-glutamate neurotransmission. Bioorg Med Chem 4:165-78 |
| Stevenson, P J; Hamelijnck, M A; Kadaba, P K et al. (1991) Triazolines. XXIII. High-performance liquid chromatographic assay in rat blood for a novel triazoline anticonvulsant (ADD17014). J Chromatogr 563:419-26 |
| Stevenson, P J; Hauksdottir, R; Kadaba, P K et al. (1990) Triazolines. XXII. Chromatography of 1-phenyl-5-(4-pyridyl)-delta 2-1,2,3-triazolines and related 1,2,3-triazoles, a new class of anticonvulsant agents. J Chromatogr 533:248-54 |
