Antinociceptive activity of derivatives of improgran and burimamide.

Improgan, a compound related to H2 and H3 antagonists, induces antinociception in rodents after intraventricular administration. Characteristics of improgan and its congeners include: (a) morphine-like antinociception on thermal and mechanical tests in two species; (b) no impairment of motor coordination or locomotor activity; (c) evidence for a novel, nonopioid mechanism that is independent of known histamine receptors; (d) lack of tolerance with daily dosing; and (e) unique structure-activity relationships (SARs). Presently, the antinociceptive activity of several new derivatives of improgan was investigated in rats. Among compounds similar to burimamide, VUF4577 (possessing a two-carbon side chain) and VUF4582 (an N-phenyl derivative of VUF4577) induced complete, dose- and time-dependent antinociception on the hot-plate and tail-flick tests with no behavioral side effects. These compounds (with ED50 values of 71-117 nmol) were approximately twice as potent as burimamide itself (a four-carbon derivative). Two other derivatives in which the thiourea group (C=S, known to cause human toxicity) was replaced by either nitroethene (C=CH-NO2, VUF5405) or urea (C=O, VUF5407) also showed effective, potent antinociception on both assays. The latter compound is the most potent improgan-like drug discovered to date (ED50 = 71 nmol). Furthermore, positional isomers of antinociceptive compounds either lacked activity (VUF5394) or induced toxicity (VUF5393), revealing a high degree of pharmacological specificity. Although the mechanism of improgan antinociception remains unknown, the present results show promise for the further development of safe, effective, and potent pain-relieving compounds.