ASPARTIC-ACID CONJUGATES OF -(3-AMINOPHENYL)-2-(1-PYRROLIDINYL)ETHYL]ACETAMIDE - KAPPA-OPIOID RECEPTOR AGONISTS WITH LIMITED ACCESS TO THE CENTRAL-NERVOUS-SYSTEM

Aspartic acid conjugates of -(3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]a cetamide (5) were synthesized and evaluated in mice for antinociceptiv e activity by intravenous and intracerebroventricular routes of admini stration. The intravenously-administered alpha-conjugate of L-Asp (2), its D-Asp diastereomer (3), and the beta-conjugate of L-Asp (4) were found to be 11-, 31-, and 40-fold, respectively, less effective than t he parent ligand 1 (ICI 199,441) in producing central nervous system m ediated antinociception in the mouse abdominal stretch assay. In addit ion, iv-administered 2 and 3 were found to also produce potent antinoc iception in the tonic phase of the mouse formalin assay, which is a mo del of tonic rather than acute pain. This study suggests that the atta chment of a zwitterionic moiety to a position in the molecule that exh ibits bulk tolerance is a viable strategy for the design of peripheral ly-selective and peripherally-active opioids.