Everette L. May

Antinociceptive action of nicotine and its methiodide derivatives in mice and rats

1 Three quaternary methiodides of nicotine were prepared and tested for antinociceptive activity in the mouse tail‐flick, mouse phenylquinone and rat tail‐flick tests. 2 Following peripheral administration, all three methiodides were inactive in the mouse and rat tail‐flick procedures, whereas nicotine was active in both tests, which suggested that nicotine was acting centrally. 3 Quaternization of nicotine did not eliminate antinociceptive activity as demonstrated by the intraventricular injection of the methiodides in mice. Nicotine pyrrolidine and bis methiodides were somewhat more potent than nicotine, whereas nicotine pyridine methiodide was considerably less potent than nicotine in the tail‐flick procedure. 4 Systemically administered nicotine pyrrolidine methiodine was approximately one‐third as active as nicotine in the mouse phenylquinone test; nicotine pyridine methiodide and nicotine bis methiodide were 100 and 300 times less active, respectively. 5 Hexamethonium partially blocked nicotine and nicotine pyrrolidine methiodide, whereas mecamylamine blocked nicotine completely but nicotine pyrrolidine methiodide partially. Nicotine may have both central and peripheral actions in the mouse phenylquinone test, whereas nicotine pyrrolidine methiodide may have both nicotine and non‐nicotine like antinociceptive activity. 6 The radiolabeled methiodides were synthesized and their disposition in body tissues studied. The methiodides were found to penetrate brain poorly (plasma‐to‐brain ratios > 20). 7 The methiodides were metabolized to nicotine to a small extent. This metabolism occurred to a greater extent in mice than in rats.

Antinociceptive studies of the optical isomers of N-allylnormetazocine (SKF 10,047).

In the mouse tail-flick test, neither the racemate of N-allylnormetazocine (NANM) nor its optical isomers showed antinociceptive activity. However, all three antagonized morphines tail-flick effects. In the phenylquinone test in mice, the racemate and (-)-isomer of NANM showed agonist activity and antagonized morphine-induced antinociception. The (+)-isomer was inactive. The opioid antagonist, naloxone was effective versus morphine alone in the tail-flick and versus morphine, and (+/-)- and (-)-NANM in the phenylquinone test. Yohimbine, the alpha 2-receptor blocker, antagonized morphine in the tail-flick test. In the phenylquinone test, yohimbine was effective versus (+/-)- and (-)-NANM, but showed no activity versus morphine. The results suggest that morphine and NANM are acting at different sites. In addition, different alpha 2-adrenoceptors appear to be involved. Some implications regarding the analgesic and psychotomimetic properties of NANM are discussed.

The Committee on Problems of Drug Dependence: A legacy of the National Academy of Sciences. A historical account

The history of The Committee on Problems of Drug Dependence is traced from its beginning (1929) as The Committee on Drug Addiction to 1989, its sixtieth anniversary. A brief account of the etiology of The Committee from The Bureau of Social Hygiene, established in New York City by John D. Rockefeller, Jr. in 1913 is also given.

Pharmacological effects of 1,2,3,5,6,10b-hexahydropyrido[2,3g]indolizine, a bridged-nicotine analog.

The racemate of a bridged-nicotine (BN) analog was synthesized and resolved into its enantiomers for pharmacological comparisons to (+)- and (-)-nicotine. The EC50 values for (-)- and (+)-nicotine and (-)- and (+)-BN were 4, 170, 53 and 400 microM, respectively, for producing contractions of guinea-pig ilea. (-)-Nicotine was an effective antinociceptive agent in the mouse tail-flick procedure at i.v. doses of 0.1-0.3 mg/kg, whereas the isomers of BN failed to alter tail-flick response in doses up to 5 mg/kg. (-)-Nicotine (0.01-0.3 mg/kg, i.v.) increased blood pressure and decreased heart rate in anesthetized rats. Neither (+)- nor (-)-BN altered blood pressure and heart rate in rats in this dosage range. At doses of 3-100 mg/kg, (+)-BN produced an increase in blood pressure without changing heart rate, while (-)-BN decreased both blood pressure and heart rate. Bridging the pyrrolidine and pyridine rings decreased biologic activity and did not result in stereoselectivity greater than that observed with (+)- and (-)-nicotine. It appears that there may be subpopulations of nicotine receptors to which the isomers of BN do not interact.

Historical introduction and review of chemistry.

A historical introduction and review of the chemistry of the agonist-antagonist analgesics is presented. This development of strong analgesics with a lowered abuse potential from nalorphine to the clinically useful agonist-antagonists pentazocine, butorphanol, nalbuphine and buprenorphine is discussed in detail. The discovery of the pure antagonist naloxone and naltrexone is described. The possible use of cyclazocine and later naltrexone in treatment of post-dependent narcotic addicts is also described. Finally, structure-activity relationships are summarized relating changes in N-alkylation to the production of narcotic antagonist activity over all of the structural types of opioids.

N-(Trifluoromethyl)benzyl substituted N-Normetazocines and N-Norketobemidones

To further investigate the unusual profile of N-benzyl substituted opioids, N-trifluoromethylbenzyl normetazocines and norketobemidones were prepared. The introduction of trifluoromethyl substituents on the benzyl group of the (-)-metazocines reduced affinity at all three receptors, with the greatest loss at kappa receptors. Surprisingly, some of the (+)-normetazocines actually possessed higher affinity than the corresponding (-)-isomers. In the ketobemidone series, the effects were different-the 4-trifluoromethyl substituted ketobemidone actually possessed 3-fold higher mu affinity than the unsubstituted parent to give a ligand with good mu affinity. In functional in vitro assays, this compound was a weak antagonists, but in apparent contradiction it was inactive in in vivo assays.

Reinforcing and phencyclidine-like stimulus properties of enantiomers of metazocine

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.