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 (B_max) rather than an altered affinity of the radioligand for receptor (K_d). 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.