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A homologous series of TV-substituted 2′-hydroxy-5- methyl-9a-propyl-6,7-benzomorphans (hydrogen to octyl inclusive, allyl, and cyclopropylmethyl) was prepared. In contradistinction to the nor-metazocine, normorphine, and (—)-3-hydroxymorphinan series, the N-pentyl and TV-hexyl derivatives do not have the analgesic potency of the parent TV-methyl compound; instead, they are narcotic antagonists with a long duration of action. All of the N-substituted 9α-propylben-zomorphans, except for methyl, heptyl, and octyl, have antagonist activity. The receptor binding constants of the TV-alkyl compounds are uniformly two- to threefold lower than those of the TV-substituted nor-Narcotic analgesics based on fused ring systems, such as the 6,7-benzomorphans and the more complex morphinans and morphines, have commonly been converted to antagonists by modification of the N-substituent (1, 2) [classically by replacing the N-methyl with allyl (3), cyclopropylmethyl (1), or propyl (1)]. Many antagonists metazocines.

Rats were trained to discriminate 200 or 400 µg/kg (-)nicotine from saline in a two-bar operant paradigm. Dose-response relationships for optically pure (-)- and (+)nicotine as well as antagonistic effects were examined in both groups of rats. The natural isomer (-)nicotine was approximately nine-times more potent than (+)nicotine. Mecamylamine produced equal blockade of the (-)- and (+)nicotine cues. Hexamethonium and atropine were without effect. These data demonstrate the possible stereospecificity of the central nicotinic receptor that mediates the stimulus effect produced by nicotine.

2,5-Dimethyl-2′-hydroxy-9α-(3-methylbutyl)-6,7-benzomorphan, the 9β-analogue, and 9α-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9β N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9α-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9αseries had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9α-(3-methylbutyl) moiety, unlike bulky substituents in the 9βposition of 6,7-benzomorphans, generally lowers affinity for the μ opioid receptor and diminishes their in vivo activity as agonists or antagonists.

Several compounds which represent classifications of drugs known to have effects on muscular efficiency were administered to dystrophic animals in which atrophy was achieved utilizing a vitamin E-deficient diet. A myopathic mutation of the house mouse (dystrophia muscularis) was also utilized in certain portions of the study. Motor coordination, weight, muscle strength, and urinary creatine and creatinine were measured. The effects of some of the compounds on the isolated diaphragm muscle of normal and dystrophic mice were also studied. Norethandrolone, methimazole, and digoxin increased the ability of vitamin E-deficient rats to perform forced motor activity. The same compounds increased the offspring survival rate of vitamin E-deficient female rats. Potassium chloride (10 mg./Kg./day) temporarily increased the mean rotarod performance time and arrested loss of weight of dystrophic mice. Although there was no statistical difference between the life span of the control and drug-treated groups of strain-129 mice, the group receiving digoxin, 0.05 mg./Kg. subcutaneously, twice a week survived the longest.

Aqueous extracts of Piper methysticumForst, were tested for pharmacological activity. The roots of this plant have been used by the natives of many of the islands of the South Pacific in a beverage known as Kava to allay anxiety and reduce fatigue. The extracts were shown to have a depressant action on the central nervous system, evidenced by depression of spontaneous motor activity, marked reduction in irritability of rats having bilateral septal lesions, inhibition of the conditioned avoidance response in rats, and blockade of EEG arousal patterns in cats.

The conditioned emotional response (CER) testing procedure was utilized as a drug screening test. Two control compounds, chlorpromazine and reserpine, and one experimental compound 5-(O-methoxyphenoxy-methyl)-2-oxazolidinone, were tested in various doses in the CER program. None of the drugs produced an attenuation of the “anxiety” response in the rat. It would appear that the CER program, as presented in this study, is not suitable as a screening procedure for the evaluation of potential ataractic agents.

Writhing was produced in mice by injecting them intraperitoneally with phenylquinone either 10 or 20 min before the start of scoring. The activity of two antiwrithing agents was compared: morphine and nalorphine at doses of 0.5 and 2.0 mg/kg injected subcutaneously 10, 20, or 40 min before scoring. Analyses of both quantal and graded data indicated that the antiwrithing activity of nalorphine decreased faster than that of morphine over time and that the slopes of the dose-response lines for nalorphine were flatter than those for morphine.

Male Wistar rats were subjected to a variable stress program 6 days per week, 4 hours per day. The blood pressure of all animals markedly increased with the peak pressor response occurring during the 11th week. There was no significant difference between the blood pressures of rats receiving saline, 1.0 ml/kg, i.p.; reserpine phosphate, 0.1 mg/kg, i.p.; and chlorpromazine hydrochloride, 4 mg/kg, i.p. Both compounds not only failed to decrease the pressor effects induced by the stressors but also appeared to potentiate the lethal effects of the Stressors. Reserpine increased mortality to stress by over 200% and chlorpromazine increased the mortality rate by approximately 100%. All stressed animals dying during the experiment demonstrated marked vacuolization of the three layers of the adrenal cortex with severe congestion of the sinusoids of the zona reticularis. The reserpine treated animals also demonstrated possible necroses of the outer layers of the zona fasciculata.

α-(-)-, (+)-, and (−)-N-4-Methylpentyl-, (-)- and (+)-N-cis-3-chloroallyl-, and (-)- and (+)-N-propynyl-N-normetazocine (I, II, and III, respectively) have been prepared from α-(-)-, (+)-, and (−)-N-normetazocine (IV) and tested for antinociceptive activity in mice and in morphine-dependent rhesus monkeys. The results obtained with Ia and b somewhat resemble the results obtained with the corresponding phenazocine isomers, whereas those observed with IIa and b more nearly correspond with those reported for (+)- and (-)-N-allyl-N-normetazocine (SKF 10,047; NANM). The propynyl isomers (IIIa and b) display profiles of activity more closely like the corresponding isomers of metazocine. Evidence is considered which suggests that some of the (+)-isomers merit closer scrutiny in animal and human studies.

Platinum-oxide hydrogenation of 5-m-methoxyphenyl-2-methyl-9-oxomorphan (I) gave the 9α-hydroxy racemate (II) whose phenolic analogue (III) is a strong antinociceptive agent, fully supportive of morphine dependence in rhesus monkeys. The di-O-acetyl derivative (VI) of III was similar to III in its profile of activity. The diastereoisomer of III (VII), obtained by hydrogenation of the methobromide of I (IV), extrusion of methyl bromide, and O-demethylation of the resultant free base (VIII), was almost inactive antinociceptively and did not suppress withdrawal symptoms in morphine-dependent monkeys. The orientation of the C-9 hydroxyl groups was deduced from spectral data and by analogy.

The preparation of 4, 4-ditritio-(+)-nicotine (Vb) (specific activity 10.3 Ci/mmole) from (+)-nicotine (Ib) via(-)-4, 4-dibromoco-tinine (IIIb) is described. Although Ibis 10-30 times less potent than (-)-nicotine (Ia) in the CNS, its binding affinity for the crude mitochondrial or nuclear fraction of whole rat brain is only three times less than that of la. However, distribution studies showed that the maximum brain levels of (-)-[3H]nicotine are nearly twice those of (+)-[3H]-nicotine following administration of a 2-μg/kg dose. Binding affinity and disposition of the stereoisomers account for a portion of the pharmacological stereospecificity of nicotine.

From a public health point of view, cocaine (COC) presents serious clinical problems and deaths from overdose and lifelong addiction patterns, not to mention its involvement in crime, in the United States. This study subjected rhesus monkeys to one intravenous administration of COC (1 mg/kg), which closely imitates the smoking of “crack” COC with regard to dose and effect. We monitored plasma concentrations over time, beginning when the primates were in a state of hyperarousal. Blood was sampled at 1, 6, 12, and 40 min after dosing. Plasma concentrations of COC decreased rapidly with a half life of 15.7 min. Mean COC concentrations in the drug-treated group (n = 7) for the four timepoints were 296, 225, 187, and 80 ng/mL, respectively. Ecgonine methyl ester (EME) concentrations ranged from 57 to 91 ng/mL. When compared with the 1-min COC concentrations, the mean EME concentration was 30.7%. Benzoylecgonine (BZE) ranged from 34 to 42 ng/mL, and the mean concentration was 11.5% of the mean COC concentration at 1 min. EME and BZE concentrations did not vary appreciably over the time course of the study. Plasma norcocaine concentrations were less than the limit of detection of 25 ng/mL. Because a rapid decline in plasma COC concentrations over time was observed along with a very small change in EME and BZE concentrations, we attribute tissue redistribution of COC, particularly to the brain, as significant and metabolism or hydrolysis of COC as minor.