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Biomedical subjects

M D Aceto

Publications and source records attributed to M D Aceto.

At least 55 records · Page 3Linked to original sources
PubMed1985

Pharmacological actions of the racemic and the enantiomeric 1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benz azo nines (C-homobenzomorphans).

The racemate and optical isomers of the C-homobenzomorphans, 1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzaz onine, were evaluated in a number of assays sensitive to narcotics of different types. All three C-homobenzomorphans were active in vitro in guinea pig ileum, mouse vas deferens, and rat brain membrane binding assays, but were of low potency. These C-homobenzomorphans showed different profiles of in vivo activity. The (+)-isomer and racemate were active as agonists in the tail-flick assay, whereas the (-)-isomer was inactive. At higher doses, the (-)-isomer and the racemate behaved as antagonists of morphine in the tail-flick assay. All three compounds were active in the phenylquinone test, but naloxone did not block this effect. In addition, all three were potent in the hot-plate test. Neither of the isomers substituted for morphine in dependent rats or monkeys. However, the (+)-isomer precipitated withdrawal in these monkeys. The (-)-isomer produced opioid-like physical dependence in both rats and monkeys. Some of the implications regarding the results with these remarkable homobenzomorphans are discussed.

Analgesics↗
PubMed1984

Agonist-antagonist actions and stereoselectivity of optical pairs of some N-substituted alpha-N-normetazocines.

alpha-(-)-, (+)-, and (+/-)-N-4-Methylpentyl-, (-)- and (+)-N-cis-3-chloroallyl-, and (-)- and (+)-N-propynyl-N-normetazocine (I, II, and III, respectively) have been prepared from alpha-(-)-, (+)-, 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.

Analgesics↗
PubMed1984

9 alpha- and 9 beta-Hydroxyphenylmorphans.

Platinum-oxide hydrogenation of 5-m-methoxyphenyl-2-methyl-9-oxomorphan (I) gave the 9 alpha-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.

Analgesics↗
PubMed1984

Similarity between (+)-amphetamine and amfonelic acid.

Rats, trained to discriminate the CNS stimulant (+)-amphetamine (1.0 mg/kg) from saline in a two-lever drug administration task, were challenged with various doses of the structurally dissimilar CNS stimulant amfonelic acid. Amfonelic acid was found to substitute for the amphetamine stimulus and was found to be 1.5 times more potent than amphetamine.

Animals↗
PubMed1984

Characterization of prototypical opioid antagonists, agonist-antagonists, and agonists in the morphine-dependent rhesus monkey.

In non-withdrawn maximally-dependent rhesus monkeys, both naloxone (NOX) and nalorphine (NAL) precipitated withdrawal when given 2 h after morphine (M). When these drugs were given 15 h after M, at which time the animals were in severe withdrawal and M blood levels were much lower, they promptly exacerbated withdrawal. Thus, mu antagonists may act competitively in non-withdrawn addicts and noncompetitively in withdrawn subjects. Buprenorphine (BRN), the partial mu agonist, precipitated withdrawal in stable addicts and partly suppressed withdrawal signs in abstinent addicts. Finally, ethyl-ketocyclazocine (EKC), the purported kappa agonist, did not precipitate but partly suppressed withdrawal at doses producing severe side effects. Perhaps this suppression is associated with kappa activity.

Animals↗
PubMed1984

Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues.

2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan (3a) has been synthesized from 5-(m-methoxyphenyl)-2-methyl-9-oxomorphan (4) and resolved into its enantiomers (+)-3a and (-)-3a. The assigned alpha-orientation of the 9-methyl group was derived from studies of induced NMR shifts using Eu(fod)3-d27. Compound (+)-3a has inappreciable agonist (antinociceptive) activity in mice, and (-)-3a shows codeine-like potency in the hot-plate and writhing tests only. The 9-demethyl homologues, (+)-1 and (-)-1, are strong agonists, about as potent as morphine in these tests as well as in the tail-flick assay. The racemic compound 3a and (+)-3a, but not (-)-3a, exhibit low-potency, narcotic-antagonist activity in mice (tail-flick test, vs. morphine). All three, however, precipitate abstinence in nonwithdrawn, morphine-dependent rhesus monkeys. Monkey studies with the 9-demethyl homologues confirmed earlier results showing that (+)-1, suppressing abstinence in withdrawn animals, has high physical dependence capacity, while (-)-1 has none. Instead, (-)-1 precipitates abstinence in nonwithdrawn animals. Studies in rats and isolated organs (guinea pig ileum and mouse vas deferens) and receptor-binding assays confirm the quite different opioid-action profiles of (+)-1 and (-)-1, which thus might interact with different opioid receptors. Catalytic hydrogenation of the methiodide (7) of 5 gave, instead of the expected epimer of 3a, ring-opened compound 8.

Analgesia↗
PubMed1983

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 morphine's 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.

Analgesics↗
PubMed1983

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 2. Non-glycolates.

The 19 esters in Table I were prepared from (+)-2 alpha-tropanol, (-)-2 beta-tropanol, (+/-)-3-quinuclidinol, and a variety of non-glycolic acids in order to compare their central and peripheral activities with those of the glycolates reported in the previous paper. The results (Table II) showed that esters 6 and 17 were approximately equivalent to one another and to atropine, that 8 was equal in both central and peripheral activity to reference glycolates, that 9 and 19 were less active than 8 but 9 had a substantially reduced central activity, and that 10 and 11 were more active than the methoxy analogue reported earlier.

Animals↗
PubMed1983

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

Three quaternary methiodides of nicotine were prepared and tested for antinociceptive activity in the mouse tail-flick, mouse phenylquinone and rat tail-flick tests. 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. 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. 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. 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. The radiolabelled methiodides were synthesized and their disposition in body tissues studied. The methiodides were found to penetrate brain poorly (plasma-to-brain ratios greater than 20). The methiodides were metabolized to nicotine to a small extent. This metabolism occurred to a greater extent in mice than in rats.

Analgesics↗
PubMed1983

Zomepirac: preclinical narcotic abuse liability evaluation.

5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate dihydrate (Zomepirac, Zomax) was assessed in a variety of preparations in which narcotic agonists and antagonists have distinctive profiles. Zomepirac failed to displace tritiated etorphine significantly at concentrations up to 200 mumol/l. It was active (3-7 X 10(-5) mol/l) on both the electrically stimulated guinea pig ileum and mouse vas deferens but was less efficacious than morphine; these effects were not reversed by narcotic antagonists. Zomepirac was inactive in some analgesic assays in mice: tail-flick (1-30 mg/kg s.c.); hot plate (1-100 mg/kg s.c.); Nilsen (1-50 mg/kg s.c.); it was also inactive (1-10 mg/kg s.c.) as an antagonist of morphine in the tail-flick assay. It was, however, active in the paraphenylquinone writhing assay; this action was not reversed by naloxone (1-10 mg/kg) Zomepirac (2.5-10 mg/kg s.c.) failed to suppress signs of withdrawal produced by morphine deprivation in dependent rhesus monkeys. The intraperitoneal infusion of high doses of zomepirac (50 mg/kg/24 h or more) in rats produced toxicity. However, lower doses failed to induce narcotic-like dependence over a 6-7-day infusion period. The compound failed to maintain intravenous drug self-administration responding in rhesus monkeys over a range of doses (0.1-3.2 mg/kg) although codeine did so. In rhesus monkeys trained to discriminate narcotic agonists (etorphine or ethylketazocine) from saline, zomepirac (1-10 mg/kg i.m.) failed to produce drug-appropriate responding. Thus, zomepirac appears to possess few, if any, of the characteristic actions of narcotics that are associated with their abuse liability.

Analgesics, Opioid↗
PubMed1983

Relationship of the biodisposition of the stereoisomers of nicotine in the central nervous system to their pharmacological actions.

The stereoisomers of nicotine were evaluated for their effectiveness in producing antinociception and altering spontaneous activity and Rotarod performance in rats. (-)-Nicotine was found to be 6, 15 and 30 times more active than its unnatural enantiomer, (+)-nicotine, in the spontaneous activity, Rotarod and antinociceptive tests, respectively. Biodispositional studies revealed that the time course (-)-[3H]nicotine closely paralleled the time course of effects on spontaneous activity and Rotarod performance but not antinociception, which suggested that multiple mechanisms were involved in the actions of nicotine. In addition, the distribution studies showed the brain and plasma levels of (-)-[3H]nicotine were higher than those of (+)-[3H] nicotine, which indicate that the pharmacological stereoselectivity of nicotine is less than originally determined. Finally, the greatest difference in the regional localization in brain of the stereoisomers was found in cerebral cortex, hippocampus and corpus striatum.

Analgesia↗