Pharmacologic and behavioral effects of EMD 28422: a novel purine which enhances (3H) diazepam binding to brain benzodiazepine receptors.

A novel purine, (N6-2-(4-chlorophenyl)-bicyclo 2.2.2.-octyl-(3)-adenosine) EMD 28422 increases the binding of (3H) diazepam to benzodiazepine receptors in vivo within 10 min after intraperitoneal administration. This increase in (3H) diazepam binding is due to an increase in the number of benzodiazepine receptors (Bmax) rather than an altered affinity of the radioligand for receptor (Kd), EMD 28422 protects mice against pentylenetetrazole and caffeine-induced seizures and potentiates the anticonvulsant action of subeffective doses of diazepam in a dose-dependent fashion. Furthermore, EMD 28422 also produces a significant increase in punished responding in a conflict situation (rats), and a long-lasting, dose-dependent decrease in spontaneous motor activity (mice). In contrast, neither EMD 39011 nor adenosine (the two component molecules of EMD 28422) possess anticonvulsant properties at doses up to five mole-equivalents of EMD 28422. These data indicate that the purine EMD 28422 produces a spectrum of pharmacologic effects similar to the benzodiazepines, yet in contrast to the benzodiazepines (and other purines), increases benzodiazepine receptor number. Thus, EMD 28422 may represent the prototype of a class of synthetic purines exerting a unique neurochemical effect on benzodiazepine receptors and possessing several therapeutic actions of the benzodiazepines.