At the present time there is no medication available to patients with moderate to severe pain with the following characteristics: No physical drug dependence liability, little or no oral or overdose lethality, little or no effects on respiratory centers, orally potent, and long acting. In this project we propose to prepare and pharamacologically evaluate six nitrogen analogs of Delta9-Tetrahydrocannabinols (THC's) including two water soluble derivatives. These compounds are designed and modeled after the active principal of Cannabis Sativa because THC's are relatively unique among drugs acting on the central nervous system (CNS). Natural products THC's are unique because (a) they contain no elemental nitrogen in their molecular structures; (b) they are not lethal to laboratory animals when administered orally; (c) they show little or no respiratory effects; and (d) though they exhibit marked CNS and some cardiovascular effects (euphoria and tachycardia), neither cannabis nor THC's have ever been reported to result in physical addiction or lethality, despite centuries of use and abuse of the natural product. Preliminary results from these laboratories (10 patients) with a related nitrogen analog in a double blind crossover relative potency assay in post-operative pain due to cancer, has already shown pain relief which is six times the potency of codeine. Following twenty years of research on the general chemistry, pharmacology and structure activity of new chemical substances derived from the cannabinoid nucleus, it is the specific aim of this project to (1) synthesize and study the detailed anti-nociceptive, pharmacological profile of four carefully selected nitrogen analogs having phenylethyl amine chemical moities found in narcotic-like analgesics, and (2) choose one of these for follow-on, in-depth, Phase II funding and study as a potentially marketable unique product for use in post-operative pain, arthritic pain, dental pain and other pain models for the aged.
