Herbert Merz

Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists☆

Naltrexone methylbromide and naloxone methylbromide, quaternary derivatives of naltrexone and naloxone respectively, are assumed to act peripherally. Both compounds reversed the intestinal stimulating effect of morphine in the dog. Naltrexone methylbromide 5 mg/kg s.c. blocked morphine-induced intestinal spike potentials for 50 min while intravenous doses caused antagonism for only 25 min. The antagonism by the s.c. route approximated that produced by naltrexone 0.2 mg/kg s.c. In morphine-dependent dogs, naltrexone methylbromide did not appear to antagonize morphine centrally in doses ranging from 0.25 to 50 mg/kg s.c. since it did not induce behavioral signs of narcotic withdrawal. Similarly, i.v. naloxone methylbromide was also able to reverse morphine-induced intestinal spike potential in dogs but the protection lasted only 25 min. In rats, naltrexone methylbromide 10 and 30 mg/kg i.p. neither reversed morphine block of PGF2 alpha-induced diarrhea nor antinociception. This suggests a lack of CNS narcotic antagonism in both test. In mice, naltrexone methylbromide, 60-720 mg/kg orally and 3-140 mg/kg i.p. failed to block morphine inhibition of prostaglandin F2 alpha-induced diarrhea. Paradoxically, in this species, 30 mg/kg s.c. of naltrexone methylbromide appeared to cross the blood-brain barrier since this dose reversed morphine-induced antinociception. In conclusion, naltrexone methylbromide effectively antagonizes the acute gut stimulating effect, but not the chronic behavioral effect of morphine administration in dogs. Based upon the antinociception test, naltrexone methylbromide does not cross the blood-brain barrier in rats but may in mice. Morphine inhibits prostaglandin F2 alpha-induced diarrhea by a central mechanism in rodents.

Irreversible Activation of the Opiate Receptor of Neuroblastoma × Glioma Hybrid Cells by an Alkylating Benzomorphan Derivative

Abstract: The benozomorphan derivative (‐) ‐ 2 ‐[2 ‐ (p ‐bromoacetamidophenyl)ethyl] ‐ 5,9α ‐ dimethyl ‐ 2’‐ hydroxy ‐ 6,7 ‐ benzomorphan (BAB), capable of reacting with nucleophilic groups, acts on neuroblastoma × glioma hybrid cells as a potent, irreversible opiate agonist. Its potency in inhibiting the increase in cellular cyclic AMP, evoked by prostaglandin E1, is comparable to that of Leu‐enkephalin. This also applies to its capacity to compete with [3H]d ‐ Ala2 ‐ Met ‐ enkephalinamide ([3H]DAEA) in binding on cell membrane preparations. The comparatively lower potency of (‐) ‐ 2 ‐ [2 ‐ (p ‐acetamidophenyl) ‐ ethyl]‐5,9α ‐ dimethyl‐2′‐hydroxy‐5,7 ‐ benzomorphan (AB), which differs from BAB in the substitution of the bromoacetamido group by an acetamido group, is of the same order of magnitude as that of morphine. The covalent interaction of BAB with the opiate receptors is deduced from the observations that (1) it is not possible to wash away this compound from the receptors, (2) the potency of BAB in inhibiting the specific binding of [3H]DAEA increases with prolonged preincubation time, and (3) AB behaves as a reversible agonist.