morphinans and metazocine

Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh2(S-TFPTTL)4, is an exceptionally efficient catalyst for enantioselective aminations of silyl enol ethers derived from acyclic ketones or alpha,beta-enones with [N-(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN=IPh), providing N-(2-nitrophenylsulfonyl)-alpha-amino ketones in high yields and with enantioselectivities of up to 95% ee. The effectiveness of the present catalytic protocol has been demonstrated by an asymmetric formal synthesis of (-)-metazocine.

Topics: Amination; Catalysis; Ethers; Molecular Structure; Morphinans; Organometallic Compounds; Rhodium

We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis.

Topics: Amination; Analgesics, Opioid; Benzomorphans; Morphinans; Pentazocine; Stereoisomerism

The inhibitory potency of opioids belonging to different structural categories on electric eel and rat brain acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) was investigated. The phenylazepine meptazinol, the pyrrolo-[2,3-b]-indole derivative eseroline and the benzomorphan normetazocine were the most potent inhibitors of AChE among the compounds tested. These were followed by (-)-metazocine, N-allylnorcyclazocine, 3-(1,3-dimethyl-3-pyrrodinyl)-phenol, levallorphan, levorphanol and pentazocine. The opioids which inhibited horse serum BuChE were in order of potency: meptazinol, methadone, profadol, levallorphan and 1,2,3-trimethyl-3-(3-hydroxyphenyl)-piperidine. The results of this work appear consistent with the fact that the anticholinesterase activity of the opioids is not confined to specific structural categories, although conformationally constrained molecules, like those of morphinans, benzomorphans or pyrrolo-[2,3-b]-indoles, appear to favour affinity for AChE, whereas highly flexible molecules, like those of acyclic opioids, inhibit BuChE in a rather selective way. In all cases, the inhibitory action of opioids markedly differed from that of carbamates or organophosphorous compounds, in that it was time-independent and immediately reversible on dilution. In general the anticholinesterase action of opioids does not seem to influence appreciably the pharmacological properties of the drugs since it is evidenced at drug doses higher than those which are analgesic. However, in the case of mixed agonist/antagonist opioids with rather weak analgesic activity, the enzyme inhibition caused by the levels of circulating drugs can be so marked as to exert also a cholinergic component of action.

Topics: Acetylcholinesterase; Analgesics; Analgesics, Opioid; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cyclazocine; Dose-Response Relationship, Drug; Electrophorus; Horses; Models, Molecular; Morphinans; Morphine; Narcotics; Rats

SH-SY5Y (human neuroblastoma) cultured cells, known to have mu-opioid receptors, have been used to assess and compare the ability of eight representative mu-selective compounds from diverse opioid families to recognize and activate these receptors. A wide range of receptor affinities spanning a factor of 10,000 was found between the highest affinity fentanyl analogs (Ki = 0.1nM) and the lowest affinity analog, meperidine (Ki = 1 microM). A similar range was found for inhibition of PGE1-stimulated cAMP accumulation with a rank order of activities that closely paralleled binding affinities. Maximum inhibition of cAMP accumulation by each compound was about 80%. Maximum stimulation of GTPase activity (approximately 50%) was also similar for all compounds except the lowest affinity meperidine. Both effects were naloxone reversible. These results provide further evidence that mu-receptors are coupled to inhibition of adenylate cyclase and that the SH-SY5Y cell line is a good system for assessment of mu-agonists functional responses.

Topics: Alprostadil; Analgesics; Cyclic AMP; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Fentanyl; GTP Phosphohydrolases; Humans; Meperidine; Morphinans; Naloxone; Narcotics; Oxymorphone; Receptors, Opioid; Receptors, Opioid, mu; Tumor Cells, Cultured

The present study examined the effects of morphine, the intermediate efficacy mu opioids (-)-pentazocine, (-)-metazocine, proxorphan, levallorphan, (-)-NANMY (N-allylnormetazocine) and (-)-cyclazocine, and the mu antagonist naloxone 1) in rats responding under a FR (fixed-ratio) 30 schedule before, during and after a chronic morphine regimen, and 2) in rats trained to discriminate 10.0 [10-MS (morphine sulfate)] or 3.0 mg/kg (3-MS) of morphine from saline. Under the FR30 schedule, chronic administration of morphine produced tolerance to morphine's rate-decreasing effects and conferred cross-tolerance to (-)-metazocine, proxorphan and (-)-pentazocine. However, the effects of these intermediate efficacy mu opioids could be differentiated from those of morphine on the basis of their 1) shallow dose-effect curves, and 2) large differences in the degree to which tolerance developed in individual rats. In the drug discrimination procedure, (-)-metazocine, proxorphan and (-)-pentazocine produced high levels of substitution for the 3-MS stimulus and intermediate levels for the 10-MS stimulus. In contrast to the pattern of substitution observed with morphine in the 10-MS group, the effects of these drugs were characterized by 1) shallow dose-effect curves, 2) large individual differences in the lowest dose of each drug that substituted completely for the 10-MS stimulus and 3) the failure to obtain complete substitution for the 10-MS stimulus in all of the rats tested. The behavioral profile obtained with the intermediate efficacy mu opioids (-)-NANM, levallorphan and (-)-cyclazocine was indicative of opioids with intrinsic efficacy lower than that of (-)-pentazocine, (-)-metazocine and proxorphan. Under the FR30 schedule, chronic administration of morphine produced an enhanced sensitivity to the rate-decreasing effects of (-)-NANM and levallorphan but not (-)-cyclazocine. In the drug discrimination procedure, (-)-NANM, levallorphan and (-)-cyclazocine produced high levels of substitution for the 3-MS stimulus and low levels for the 10-MS stimulus. Like naloxone, these drugs produced a dose-related attenuation of the 10-MS stimulus. The results of the present study suggest that the relative order of intrinsic efficacy among the opioids tested is: morphine > (-)-metazocine = (-)-pentazocine = proxorphan > (-)-cyclazocine = levallorphan = (-)-NANM > naloxone.

Topics: Animals; Discrimination Learning; Dose-Response Relationship, Drug; Drug Resistance; Food; Male; Morphinans; Morphine; Naloxone; Pentazocine; Rats; Receptors, Opioid, mu

A series of mu and kappa opioid agonists with varying degrees of selectivity were evaluated for their agonist and antagonist effects in squirrel monkeys trained to discriminate either the selective mu agonist fentanyl or the selective kappa agonist U50,488 from water. In the fentanyl-trained monkeys, fentanyl, as well as the less selective mu agonists buprenorphine and (-)-metazocine, produced dose-dependent and complete substitution for the training stimulus. U50,488 produced neither agonist nor antagonist effects in the fentanyl-trained monkeys, but the less selective kappa agonists bremazocine and tifluadom generally produced either agonist or antagonist effects, depending on the monkey tested. In the U50,488-trained monkeys, U50,488, bremazocine and tifluadom all produced a dose-dependent and complete substitution for the training stimulus. Fentanyl produced neither agonist nor antagonist effects in the U50,488-trained monkeys, but buprenorphine and (-)-metazocine antagonized the discriminative stimulus effects of U50,488. The inability of the selective mu agonist fentanyl and the selective kappa agonist U50,488 to antagonize each other's discriminative stimulus effects suggests that the stimulus effects mediated by mu and kappa opioid receptors in squirrel monkeys do not interact with a common biologic substrate. Rather, these results suggest that the stimulus effects mediated by mu and kappa receptors function independently of one another. Interactions involving the less selective mu agonists buprenorphine and (-)-metazocine, or the less selective kappa agonists bremazocine and tifluadom, can be explained on the basis of the low receptor selectivity of these drugs.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Behavior, Animal; Buprenorphine; Drug Interactions; Fentanyl; Learning; Male; Morphinans; Naloxone; Narcotics; Pentobarbital; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Saimiri

Topics: Animals; Benzeneacetamides; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Guinea Pigs; Ileum; In Vitro Techniques; Male; Mice; Morphinans; Pyrrolidines; Rabbits; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Vas Deferens

Topics: Chemical Phenomena; Chemistry; Models, Chemical; Models, Structural; Molecular Conformation; Morphinans; Morphine; Receptors, Opioid; Stereoisomerism

Topics: Animals; Haplorhini; Models, Molecular; Molecular Conformation; Morphinans; Morphine Dependence; Stereoisomerism; Structure-Activity Relationship

The positive reinforcing properties of the racemate and stereoisomers of the benzomorphan, metazocine, were tested in three rhesus monkeys trained to self-administer IV injections of cocaine. The (-)-isomer maintained responding above saline levels at the highest dose tested (30 micrograms/kg/injection) in two of the three monkeys. Likewise, (+)-metazocine maintained self-administration responding in two monkeys at a dose of 100 micrograms/kg/injection. Responding for (+-)-metazocine was maintained in all three monkeys at doses of 10-100 micrograms/kg/injection. The discriminative stimulus properties of the three forms of metazocine were tested in rats trained to discriminate phencyclidine (PCP; 3.0 mg/kg) from saline on a two-lever food-reinforced operant task. When metazocine was tested in these animals, only the (+)-isomer produced dose-related increases in responding on the PCP-lever. Both (+-)- and (-)-metazocine resulted in only saline-appropriate responding. Thus, the results of these two experiments demonstrate that both enantiomers of metazocine function as positive reinforcers in monkeys and further, the reinforcing properties of (+)-metazocine may be due to the PCP/sigma properties of this isomer.

Topics: Animals; Cocaine; Conditioning, Operant; Discrimination, Psychological; Injections, Intravenous; Macaca mulatta; Male; Morphinans; Narcotics; Phencyclidine; Rats; Rats, Inbred Strains; Reinforcement, Psychology; Self Administration; Stereoisomerism

Conversion of the 8-phenolic 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines to the corresponding 8-thiophenolic analogues was achieved by three different routes. Diazotization of 8-amino-2,6-methano-3-benzazocine (2) followed by the reaction with CH3SNa afforded 8-(methylthio)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (3). Another route using Grewe cyclization was also examined for the synthesis of 3. As the most effective route, Newman-Kwart rearrangement of benzazocines was selected and closely investigated. 8-(N,N-Dimethylthiocarbamoyl)oxy derivatives (6a-e) rearranged to 8-(N,N-dimethylcarbamoyl)thio derivatives (7a-e) in good yields. Reductive cleavage of 7a-e and subsequent methylation or acylations gave the title compounds (3, 8-24). Although analgesic activities of sulfur-containing benzazocines decreased compared to the corresponding hydroxy compounds, the N-methyl derivative (S-metazocine, 8) showed potent analgesic activity.

Topics: Acylation; Analgesia; Animals; Brain; Chemical Phenomena; Chemistry; Methylation; Mice; Morphinans; Morphine; Naloxone; Oxygen; Phenazocine; Rabbits; Rats; Receptors, Opioid; Structure-Activity Relationship; Sulfur