Opioid receptor antagonist affinity ligands: 6 beta-bromoacetamido-6-desoxynaltrexone and 6 beta-thioglycolamido-6-desoxynaltrexone.

The present study, utilizing thioglycolamido as the reactive group, describes the synthesis and pharmacology of a new opioid antagonist affinity ligand, 6 beta-thioglycolamido-6-desoxynaltrexone (TAN) and compares TAN with a related known compound, 6 beta-bromoacetamido-6-desoxynaltrexone (BAN). Both compounds were tested for their reversible and irreversible inhibition of [3H]naloxone binding to calf brain membranes. Reversible binding of BAN and TAN had Ki values of 1 x 10(-9) and 1 x 10(-10) M, respectively as determined by log probit plots. Irreversible binding was determined after extensive washing to remove all non-covalently bound ligand. At a concentration of 5 x 10(-8) and 1 x 10(-8) M for BAN and TAN irreversible binding was inhibited 50% of the maximum value. A study of the time course of irreversible inhibition of [3H]naloxone binding revealed that maximal inhibition occurred within 5 min with a concentration of 1 x 10(-7) M of either agent. TAN but not BAN when administered systematically to mice produced an antinociceptive effect as measured by the writhing test. When administered intracerebraventricularly BAN did not block morphine-induced analgesia for more than 2 hr; whereas, with a single ED50 dose of 20 nmoles of TAN i.c.v. morphine-induced analgesia was almost completely blocked for a period of over 24 hr, as determined by the tail flick test. Although the SH group of TAN were required for the covalent interaction with opioid receptors, the site of TAN's interaction appears to involve other than protein SH groups.