Method for comparison of the hemodynamic effects of equi-antinociceptive oral doses of drugs in anesthetized rats

In a typical flowchart for discovery of novel analgesic (or other) agents, a critical path often involves maximization of the separation of the therap eutic endpoint from known adverse-effect (AE) endpoint(s). Although strateg ies can easily be designed for in vitro paradigms such as high-throughput s creening, extension to in vivo testing can represent a major obstacle to th e rapid progression to the next step in development. The problem can be par ticularly acute when the assessment is required for oral dosing, and when i t is not known if the therapeutic and AE mechanism(s) of action are the sam e. As a case in point, alpha(2)-adrenoceptor (alpha(2)-AR) agonists have po tential therapeutic use as analgesics, but they also produce cardiovascular (CV) effects. However, whether the two effects are inexorably linked has n ot been re solved, particularly for oral administration. The present study used a novel method for comparing the CV effects produced by alpha(2)-AR ag onists given by intraduodenal administration to anesthetized rats at fixed ratios of the oral antinociceptive ED50 dose of each agonist. The technique provided a useful screen of compounds. Tn addition,there was no correlatio n between CV endpoints and alpha(2A)-AR affinity, suggesting that oral alph a(2)-AR-mediated analgesia and CV effects might be separable or that other mechanisms might be involved. (C) 2000 Elsevier Science Inc. All rights res erved.