Edward R. Bowman

Etorphines: μ-opioid receptor-selective antinociception and low physical dependence capacity

Comparative analgesic studies revealed that dihydroetorphine was more potent than etorphine in the tail-flick and hot-plate tests, respectively and nearly equipotent in the phenylquinone assay. Both compounds were short acting. Studies with selective opioid receptor antagonists beta-funaltrexamine, nor-binaltorphimine and naltrindole revealed that both etorphines were mu-selective agonists. Presumptive evidence for competitive antagonism of these compounds with naloxone was provided by Schild regressions with slopes of near unity. In a suppression test in rhesus monkeys maximally dependent on morphine, dihydroetorphine and etorphine dose-dependently replaced morphine. Drug-naive simians chronically exposed to frequent, intermittent and escalating doses of dihydroetorphine for 42 days showed few withdrawal signs when challenged with large doses of naloxone or were abruptly withdrawn from this drug. The results suggest that these atypical opioids may be useful in the clinical treatment of pain and opiate drug abuse.

Nicotine's opioid and anti-opioid interactions: Proposed role in smoking behavior

Nicotine produced antinociception in mice which was antagonized noncompetitively by naloxone. In addition, at significantly lower doses, nicotine noncompetitively antagonized morphine-induced antinociception. A speculative suggestion regarding the opiatergic and anti-opiatergic actions of nicotine is that it significantly promotes and maintains smoking behavior.

A Convenient Method for the Preparation of Racemic Nicotine

Abstract Early studies, in which the first resolution of racemic nicotine was accomplished showed2 that 1-nicotine, the principal alkaloid of tobacco, was acutely less toxic than d-nicotine in limited mammalian tests. Later studies3,4 have generally confirmed this, and some investigators suggest that the physiological effects of d-nicotine may, to some extent, oppose the effects of 1-nicotine, although this matter has been debated. It has been reported5 that racemization of 1-nicotine during the course of tobacco smoking leads to the transfer of significant quantities of d-nicotine into the mainstream of cigarette smoke. Where d,1-nicotine has been employed in insecticidal studies, data indicate6 that d-nicotine-has alethality equal to that of the-1-isomer. These species differences in response to nicotine antipodes and recent evidence of a central stereospecific nicotine receptor7,8 have stimulated inter estin efficient routes to the attainment of large quantities of-d-nicotine.

Tissue disposition of [3H]sarin and its metabolites in mice

The biodisposition and metabolic fate of [3H]sarin was investigated in mice after iv administration of a sublethal dose (80 micrograms/kg). Within 1 min of administration, all tissues contained substantial quantities of radioactivity of which less than 10% represented [3H]sarin. The major portion of radioactivity corresponded to free [3H]isopropyl methylphosphonic acid (IMPA), the pharmacologically inactive hydrolytic product of [3H]sarin. Somewhat lesser quantities were present as bound [3H]IMPA which resulted from phosphorylation of protein. Plasma contained high concentrations of bound [3H]IMPA, consistent with sarins very reactive nature, which were sustained throughout the time course. Plasma concentrations of free [3H]IMPA diminished rather quickly. The high concentrations of metabolites in kidneys implied that this organ played a major role in the detoxification and excretion of [3H]sarin. Large quantities of free and bound [3H]IMPA were also found in lung which suggested an important site for toxicity. Only trace quantities of [3H]sarin were found in brain after 15 min. The major portion of radioactivity was present as either free and bound [3H]IMPA or as nonextractable material which presumably was [3H]methylphosphonic acid. Examination of the time course of sarin-induced motor hypoactivity and hypothermia revealed an immediate onset of action that lasted for 24 hr. However, substantial quantities of bound [3H]IMPA remained in brain at 24 hr which suggested that only a small portion of phosphorylation in brain accounted for these pharmacological effects.

The appearance of endogenous opiates in cerebrospinal fluid following opiate injection in various animal species

Phenylquinone writhing, tail-flick, stimulated guinea pig ileum and mouse vas deferens were used to quantitate opiate-like activity in CSF taken prior to and at various times after the injection of morphine. The injection of various doses of morphine caused a dose responsive increase in opiate-like material in rabbit CSF taken at the peak of activity (60 min later). Morphine also caused an increase in opiate activity in dog CSF. Quantitation of radioactivity in CSF after the injection of radiolabelled morphine, stability studies and other assays were used to rule out the possibility that the increased activity in CSF was due to morphine itself. CSF taken after morphine injection produced a peak on HPLC with a 15 minute retention time which was not present in CSF taken prior to the injection. This peak was not caused by morphine, met-enkephalin, leu-enkephalin, dynorphin 1-13 or beta-endorphin which have retention times of 5, 7, 9, 22 and 30 minutes, respectively. Preinjection of the rabbit with naloxone blocked the increased opiate-like effects of CSF taken after morphine and the opiate effects of the CSF were antagonized by naloxone injected into mice or the isolated organ bath.

Comparison of the ability of opioid analgesics to increase endogenous opioid-like activity in the cerebrospinal fluid of rabbits

We have previously demonstrated that the acute administration of morphine increases the level of endogenous substances, which have antinociceptive activity, in cerebrospinal fluid (CSF). The present study was conducted to determine whether other opioid analgesics exert a similar effect. CSF was withdrawn from the cisterna magna of anesthetized rabbits before and after s.c. injections of meperidine, pentazocine, levorphanol and methadone, and was bioassayed for opioid-like activity in the mouse tail-flick and phenylquinone writhing tests. The opioid-like activity of CSF taken 60 min after meperidine (50 mg/kg) was significantly increased in both bioassays, and the CSF level of meperidine was insufficient to account for this effect. Pentazocine (25-75 mg/kg) also significantly increased opioid-like activity in rabbit CSF, but the effects of methadone (5-10 mg/kg) and levorphanol (20 mg/kg) were less marked. Dextrorphan (20 mg/kg), diazepam (10 mg/kg) and pentobarbital (20 mg/kg) administration did not significantly increase opioid-like activity in CSF. It is concluded that the antinociceptive action of some opioid analgesics in rabbits may be mediated in part by the release of endogenous antinociceptive substances.

Mammalian degradation of (-)-nicotine to 3-pyridylacetic acid and other compounds.

Summary 1. The pattern of urinary excretion of C14 in the dog following intravenous administration of (-)-nicotine-C14 has been examined chromatographically by improved procedures. 2. The fractionated urine showed C14 activity corresponding chromatographically to the known metabolites: cotinine, γ- (3-pyridyl)-γ-methylaminobutyric acid, desmethylcotinine-hydroxycotinine, and γ-(3-pyridyl)-β-oxo-N-methylbutyramide. 3. Among many unidentified radioactive components, the urine contained material corresponding chromatographically to 3-pyridyl-acetic acid. 4. Following oral administration of (-)-cotinine to the dog. 3-pyridylacetic: acid was isolated from urine and characterized by analysis, melting point, mixed melting point and as its picric acid salt. 5. A precursor of 3-pyridylacetic acid is on formal grounds γ-(3-pyridyl)-β-oxobutyric acid, derivable from the known metabolite γ-(3-pyridyl)-β-oxo-N-methylbutyramide.

The fate and distribution of 1-(3-pyridyl)ethanol methiodide in relation to the toxicity of 1-(3-pyridyl)ethanol and 3-acetylpyridine

Abstract (+,−)-N-Methyl- 14 C-3-(1-hydroxymethyl)pyridinium iodide, prepared from methyl- 14 C iodide and (+,−)-1-(3-pyridyl)ethanol, was administered intravenously to mice. Sequential whole-body autoradiograms showed a rapid elimination of the radioactivity of (+,−)-N-methyl- 14 C-3-(1-hydroxyethyl)pyridinium iodide from the animals. The compound, in common with the established behavior of many other quaternary ammonium compounds, showed no great tendency to pass the blood-brain barrier. In rats, after intraperitoneal administration, and mice, after intravenous administration, the radioactivity of (+,−)-N-methyl- 14 C-3-(1-hydroxyethyl)pyridinium iodide was eliminated largely (78–90 per cent) by way of the urine within 24 hr. This excreted radioactivity was predominantly in the form of the administered cation. The signs of acute toxicity from large doses of (+,−)-N-methyl-3-(1-hydroxyethyl)-pyridinium iodide differed from the previously well-established similarity of those arising from 3-acetylpyridine and (+,−)-1-(3-pyridyl)ethanol; and the levorotatory form of 1-(3-pyridyl)ethanol appeared to produce gross toxic effects similar to those from the racemic alcohol.

The excretion and metabolism of triethylene glycol

A method is described for the preparation of randomly labeled triethylene glycol-C14. Methods are described for the colorimetric and vapor phase chromatographic determination of triethylene glycol in urine and for the determination of trace quantities of diethylene glycol in triethylene glycol. After oral doses of triethylene glycol the rat and the rabbit excrete triethylene glycol in both unchanged and oxidized form. The data suggest that one of the oxidation products is a monocarboxylic acid which arises by metabolic oxidation of a single terminal hydroxyl group of the parent glycol. After oral administration of triethylene glycol-C14 the rat eliminated only trace quantities of C14 activity as respiratory carbon dioxide. A small but measurable amount of radioactivity was found in the feces. The total elimination of radioactivity (in urine, feces, and expired air) during the 5-day period following a single oral dose (22.5 mg) was 91–98%. The major part of the radioactivity appeared in the urine. The data from fractionation of the urine indicated that only negligible quantities (if any) of C14 were present as oxalic acid. The major metabolic products had properties which suggested that triethylene glycol is degraded by the rcute: HOCH2CH2OCH2CH2OCH2CH2OH→ HOCH2CH2OCH2CH2OCH2COOH→HOOC CH2CH2OCH2CH2OCH2COOH The foregoing data, showing a high degree of elimination of triethylene glycol and its metabolites by way of the urine, is consistent with many findings pointing to the low or limited toxicity of triethylene glycol.

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.