NEUROPHARMACOLOGIC EVALUATION OF 2-PHENYLIMIDAZO- [1,2-a] PYRIMIDINE HYDROBROMIDE (U-13,376B), AN UNUSUAL STRYCHNINE ANTAGONIST

¹ Pharmacology Research Laboratories, The Upjohn Company, Kalamazoo, Michigan

Seizures resulting from small convulsive doses of strychnine were antagonized by 2-phenylimidazo-[1,2-a] pyrimidine hydrobromide (U-13,367B). This finding was unusual for several reasons. Toxic doses of the antagonist were characterized by stimulation and convulsions rather than by depression. Also, protection occurred at doses much lower than those producing neurotoxicity. The ED50's were as follows: for strychnine protection, 62 mg/kg; for traction loss, 214 mg/kg; for electroshock protection, 123 mg/kg; and for loss of the righting reflex, 800 mg/kg. In addition, large doses of strychnine could not be antagonized by any quantity of U-13,376B. All of these findings, which are in sharp contrast to findings with other antagonists of strychnine, prompted further investigation. U-13,376B was also found to have strychnine-like properties as indicated by antagonism of caudate inhibition, potentiation of polysynaptic reflex pathways and antagonism of direct spinal inhibition. Based on estimates from these preparations, strychnine was approximately 1000 times more potent than U-13,376B. Strychnine-like properties were not apparent when U-13,376B was tested by two other methods. Latency of tonic extensor seizures elicited by electroshock treatment and electroencephalographic convulsive patterns in rabbits were not altered in a strychnine-like manner. Also, seizures following toxic doses of U-13,376B were primarily clonic rather than tonic. Most of the effects of U-13,376B can be explained by the hypothesis that it is a partial agonist of strychnine. On the other hand, elevation of electroshock seizures thresholds and the cortical pattern of seizure activity are not shared by strychnine.