The kappa opioid receptor and food intake.

Many studies have suggested a role of opioid receptors in the modulation of food intake. Several distinct classes of opioid receptors have been postulated. In an attempt to establish which opioid receptor(s) modulate feeding we studied the effect of the kappa agonist, bremazocine, on feeding and compared its effects to the preferential mu agonist, morphine, and the mixed kappa-sigma agonist, butorphanol and the kappa agonist, ethylketocyclazocine. Bremazocine increased feeding to the same extent as morphine and was less potent than the mixed agonist/antagonists. The bremazocine effect demonstrated a bell-shaped dose response curve. Daily administration of bremazocine or morphine enhances the effect on increasing food intake. However, this effect of daily injections on enhancing food intake is not present when animals receiving morphine are crossed over to bremazocine and vice versa. The bremazocine effect is enhanced by diprenorphine and not inhibited by naloxone. Low doses of the dopamine antagonist, haloperidol, enhance the bremazocine effect and higher doses inhibit it. Finally, using another kappa agonist, tifluadom, we showed that the effect on food intake is stereospecific. Our studies provided further evidence for a role for the kappa opioid receptor in feeding. However, they also suggest that more than one subpopulation of opioid receptors is involved in feeding modulation.

Metabolism and pharmacokinetics of metaclazepam (Talis), Part III: Determination of the chemical structure of metabolites in dogs, rabbits and men.

The metabolism of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2, 3-dihydro-1H-1,4-benzodiazepine (metaclazepam, Talis) in animals and men is described. Based upon mass spectrometry fifteen metabolites could be identified. Qualitative and quantitative differences in the biotransformation products of metaclazepam in comparison with the well known metabolites of other drugs in the 1,4-benzodiazepine class could be demonstrated. Metabolites with a benzodiazepine-2-one structure representing the most characteristic feature of other 1,4-benzodiazepines and their metabolites, were found in trace amounts only. The major metabolic pathways of metaclazepam led via stepwise demethylation of the O-methyl and/or the N-methyl group to O-demethyl-metaclazepam (M 2), N-demethyl-metaclazepam (M 7) and bis-demethyl-metaclazepam (M 6). Further aromatic hydroxylation yielded the metabolite M 1. Two metabolites with amino-benzophenone structure (M 5, M 8) which are in general known to result from other 1,4-benzodiazepines could be detected. Additionally a 3-oxo-benzodiazepine (M 4) was found. Minor biotransformation pathways led to a chlorophenyl-bromo-benzodiazepine (M 9) by loss of the side chain from bis-demethyl-metaclazepam and N-demethyl-metaclazepam. By further oxidation and degradation the 2-oxo-benzodiazepine M 10 and the dihydro-quinazoline M 12 were formed. The respective N-methylated metabolites M 13 and M 16 were possibly generated by the same pathway. Still open is the formation of M 15, a 1-methyl-3-hydroxy-4-(2'-chlorophenyl)-6-bromo-1,2-dihydroquinoline and M 11, a 2-methyl-4-(2'-chlorophenyl)-6-bromo-quinazoline. The substitution of bromine by a hydroxyl group during the formation of M 14 can be explained by a NIH-shift mechanism. Quantitative investigations show that the methoxymethyl side chain in the benzodiazepine ring system of metaclazepam acts as an effective barrier with respect to the metabolic attack at position two. We assume that this barrier only can be overcome by complete side chain degradation. This multi-step reaction can hardly compete with more favourable and faster conjugation and elimination processes.

The effect of the opioid-benzodiazepine, tifluadom, on ingestive behaviors.

A large body of evidence has suggested a role for the endogenous opiates and their receptors in the regulation of appetite. In this study, we report on the effects of tifluadom, a noval opiate with a benzodiazepine-like structure and preferential activity at the kappa opiate receptor, on ingestive behaviors. Tifluadom increases food intake in rats without altering water intake. Tifluadom's effect on feeding is more potent than that of morphine or ketocyclazocine and equivalent to that of butorphanol. The effect is partially resistant to naloxone antagonism. Tifluadom is more potent when administered subcutaneously than when given intraperitoneally. These data provide further support for the concept that kappa opiate receptors represent an important component of the natural feeding drive.

Effects of the opioid benzodiazepine tifluadom and its optical isomers on spontaneous locomotor activity of mice.

The opioid benzodiazepine tifluadom and its (+) and (-) enantiomers affect locomotor activity of mice with patterns different from those of diazepam or the prototype opioids morphine (mu) or bremazocine (kappa). Lacking the initial locomotor inhibition, the sum of activity of the two enantiomers does not comply with the effects of the racemic mixture, thus indicating a non-additive interaction. In addition to the opioid effects of tifluadom, the effective antagonisms to the locomotor stimulatory phase of this compound and its enantiomers by Ro 15-1788 points to some interaction with the benzodiazepine/GABA-receptor complex.

Unexpected opioid activity in a known class of drug.

Tifluadom, although structurally a 1,4 benzodiazepine, has no affinity for the 3H-flunitrazepam binding site, but is a potent displacer of 3H-bremazocine from its opioid binding site. Tifluadom is characterised as an opiate kappa-receptor agonist in vitro and in vivo with potent analgesic activity in animals and no dependence potential.