A POTENT NEW CLASS OF KAPPA-RECEPTOR AGONIST - 4-SUBSTITUTED 1-(ARYLACETYL)-2-[(DIALKYLAMINO)METHYL]PIPERAZINES

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]pi perazines (10-22, 26, 27, and 30-33) and their activities as kappa-opi oid receptor agonists are described. This includes a range of 4-acyl a nd 4-carboalkoxy derivatives with the latter series showing the greate st kappa-agonist activity. In particular, methyl yl]-3-[(1-pyrrolidiny l)methyl]-1-piperazinecarboxy late (18) displays exceptional potency a nd selectivity. It showed the following activities in functional in vi tro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 n M, rat vas deferens (mu-specific tissue) IC50 > 10 000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10 000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mous e acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 m g/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. Th e kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this re gion of the molecule is an important requirement for optimal