Pharmacological study of 14 beta-(thioglycolamido)-7,8-dihydro-N(cyclopropylmethyl)-normor phinone (N-CPM-TAMO)

Opioid effects of 14 beta-(thioglycolamido)-7,8-dihydro-N(cyclopropylmethyl)- normorphinone (N-CPM-TAMO) were studied in the mouse tail-flick and acetic acid writhing assays. In the tail-flick test, N-CPM-TAMO failed to produce any antinociception after i.c.v. administration of up to 300 nmol. However, pretreatment of mice with N-CPM-TAMO produced a time- and dose-dependent antagonism of morphine-induced antinociception. The antagonism by N-CPM-TAMO lasted up to 48 hr, with a maximal effect at 24 hr after i.c.v. administration. Similarly, pretreatment of mice with N-CPM-TAMO at 24 hr also produced a dose-dependent antagonism of kappa-mediated antinociception, induced by U50,488 However, the antagonistic potency of N-CPM-TAMO against U50,488 was 100-fold less than against morphine. Pretreatment with N-CPM-TAMO had no effect on delta opioid receptor-mediated antinociception, as measured with [D-Pen2,D-Pen5]enkephalin. In the writhing assay, N-CPM-TAMO produced a time- and dose-dependent antinociception after i.c.v. administration, with a value of the dose producing 50% analgesia of 18.4 (10.6-31.9) nmol. The antinociceptive effect lasted up to 3 hr after administration. N-CPM-TAMO-induced antinociception was antagonized by coadministration of the kappa-selective antagonist, norbinaltorphimine. Pretreatment of mice with N-CPM-TAMO also produced a time- and dose-dependent antagonism of U50,488-induced antinociception, which lasted up to 72 hr, with a maximal effect at 24 hr after administration. These data indicate that N-CPM-TAMO is a mu-selective, long-term antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)