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M D Aceto

Publications and source records attributed to M D Aceto.

At least 37 records · Page 2Linked to original sources
PubMed1991

Common stereospecificity of opioid and dopamine systems for N-butyrophenone prodine-like compounds.

The two optical isomers of 1-[3-(p-fluorobenzoyl) propyl]-3-methyl-4-phenyl-4-propionoxypiperidine (FPP) were obtained by resolution of (+/-)-r-3-methyl-4-phenyl-c-4-piperidinol followed by N-alkylation and O-propionylation. These, as well as the racemate, were evaluated for their antinociceptive, opioid, and neuroleptic properties using in vivo and in vitro test systems. The results are remarkable in two respects, namely, the dextrorotatory isomer is consistently the most potent on all tests, and it acts on both opioid (mu) and neuroleptic (D2) receptors.

Alphaprodine↗
PubMed1989

Assessment of the abuse potential of acetorphan, an enkephalinase inhibitor.

The discriminative stimulus properties, reinforcing effects and physical dependence potential of acetorphan, a parenterally-active enkephalinase (E.C. 3.4.21.11) inhibitor, were assessed in the present studies. Rats trained to discriminate 2 mg/kg morphine from saline did not generalize to acetorphan at any dose tested (5-50 mg/kg). Acetorphan also had minimal reinforcing effects in rhesus monkeys. When acetorphan was substituted for cocaine, one dose (300 micrograms/kg per inj.) maintained responding somewhat above the range of vehicle values in only two of the four monkeys tested. In physical dependence studies, acetorphan also failed to produce opioid-like effects. In morphine-dependent monkeys and rats, acetorphan failed to suppress withdrawal. Additionally, there were no overt withdrawal signs observed following the termination of chronic acetorphan infusion in the rat. Together, these results indicate that acetorphan appears to have minimal abuse potential.

Animals↗
PubMed1989

Very long-acting narcotic antagonists: the 14 beta-p-substituted cinnamoylaminomorphinones and their partial mu agonist codeinone relatives.

The biological activity of 14 beta-(p-halo and p-methylcinnamoylamino)-7,8-dihydro-N-cyclopropylmethylnorcodei nones and their corresponding morphinones was investigated. In vitro, the codeinones displayed predominantly mu agonist activity in the 3H-etorphine binding assay and mouse vas deferens preparation. In vivo, in the mouse, the compounds showed weak to inactive antinociception in the tail-flick and hot-plate tets; however, they were potent agonists in the phenylquinone test and moderately weak antagonists in the tail-flick vs morphine test. They also substituted for morphine in withdrawn morphine-dependent rhesus monkeys. When given to non-withdrawn morphine-dependent monkeys, the codeinones precipitated a delayed but long-lasting withdrawal syndrome. They all generalized to codeine in the drug-discrimination test in rhesus monkeys and, in the dose range tested, two compounds were self-administered. This activity is consistent with that of a partial mu agonist. On the other hand, all the morphinones had very long-acting and highly potent mu antagonist properties. The data can be reconciled by assuming that the codeinones are partially metabolized to their respective morphinones. These compounds may be especially useful in the treatment of opioid dependence.

Analgesics↗
PubMed1987

2,5-Dimethyl-2'-hydroxy-9 alpha- and 9 beta-(3-methylbutyl)-6,7-benzomorphans and N-substituted compounds in the 9 alpha-(3-methylbutyl) series: chemistry, pharmacology, and biochemistry.

2,5-Dimethyl-2'-hydroxy-9 alpha-(3-methylbutyl)-6,7-benzomorphan, the 9 beta-analogue, and 9 alpha-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9 beta 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 9 alpha-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 9 alpha series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9 alpha-(3-methylbutyl) moiety, unlike bulky substituents in the 9 beta position of 6,7-benzomorphans, generally lowers affinity for the mu opioid receptor and diminishes their in vivo activity as agonists or antagonists.

Analgesics↗
PubMed1987

Hexahydro-1H-1-pyrindines from acid rearrangement of 9-alkylidene-5-(m-methoxyphenyl)-2-methylmorphans. A new structural type of narcotic antagonists.

9-Methylene- and 9-ethylidene-5-(m-methoxyphenyl)-2-methylmorphans (1, 2) and refluxing 48% HBr have given rearrangement products 3 and 4, respectively. The structure of 4 [4a-ethyl-2,4a,5,6,7,7a-hexahydro-4-(3-hydroxyphenyl)-1-methyl-1H-1- pyrindine] was determined by X-ray crystallography and that of 3 [1,4a-dimethyl-2,4a,5,6,7,7a-hexahydro-4-(3-hydroxyphenyl)-1-methyl-1H- pyrindine] follows from analogy and NMR data. Compounds 3 and 4 are opioid antagonists of about the potency of nalorphine in the tail-flick vs. morphine assay and precipitate a complete abstinence syndrome in morphine-dependent monkeys. Both are nearly devoid of antinociceptive activity and they have about 0.025 times the affinity of nalorphine for the mu opioid receptor.

Alkaloids↗
PubMed1986

Rapid and brief tolerance to (+)- and (-)-nicotine in unanesthetized rats.

When given intravenously to unanesthetized rats as a bolus dose, (-)-nicotine produced a dose-related rise in blood pressure and fall in heart rate in the dose range of 5-40 micrograms/kg. Tolerance did not develop when doses were given at 30 min intervals. At the highest dose, the effects on heart rate persisted. In addition, severe arrhythmias and apnea were observed. (+)-Nicotine at 100 micrograms/kg produced effects similar to 10 micrograms/kg of (-)-nicotine. When given at 1 min intervals, tolerance quickly developed after only 6 injections at 5 micrograms/kg and after 4 injections at 10 micrograms/kg. Tolerance to (+)-nicotine also developed rapidly and was no longer evident at 5 min. The results suggest the tolerance is related to frequency of administration and dose. The implication of these results are discussed with regard to cardiovascular disease and dependence. In addition, we postulate that the relatively low degree of biological stereoselectivity of the optical isomers of nicotine, compared with that of the enantiomers of morphine, is due to the simplicity and flexibility of the nicotine molecule. It can be shown using Dreiding models that the nitrogen atoms in the enantiomers are nearly superimposable.

Animals↗
PubMed1986

Effects of beta-funaltrexamine (beta-FNA) on morphine dependence in rats and monkeys.

The opioid mu receptor antagonist beta-funaltrexamine (beta-FNA) blocked the development of physical dependence in rats when infused simultaneously with morphine for 6 days. In addition, beta-FNA given s.c. 24 h prior to the initiation and on day 3 of a 6 day period of morphine infusion in rats reduced the development of physical dependence in a dose-dependent manner. In morphine-dependent rhesus monkeys, beta-FNA precipitated a prompt and long-lasting withdrawal, which was not reversed within 30 h by subsequent injections of morphine. In contrast, naloxone-induced withdrawal lasted approximately 90 min. These results provide further evidence that beta-FNA is a long-acting antagonist of the opioid mu receptor, and that this receptor has a major role in the development of morphine-induced physical dependence.

Animals↗
PubMed1986

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.

Analgesics↗
PubMed1986

The spinal cord as a major site for the antinociceptive action of nicotine in the rat.

These studies were conducted to localize the antinociceptive action of nicotine within the CNS. Antinociceptive and biodispositional studies were carried out after the injection of [3H]nicotine subcutaneously and intracerebroventricularly into the common carotid and vertebral arteries and into the subarachnoid space. The data indicated that [3H]nicotine was most potent when given into the subarachnoid space than by any of the other route of administration. Further, the disposition studies showed that [3H]nicotine was almost entirely contained in the thoracic and lumbar areas. These results are consistent with the hypothesis that the spinal cord is an important site for antinociception induced by nicotine.

Analgesia↗
PubMed1986

Probes for narcotic receptor mediated phenomena. 13. Potential irreversible narcotic antagonist-based ligands derived from 6,14-endo-ethenotetrahydronororipavine with 7-(methoxyfumaroyl)amino, (bromoacetyl)amino, or isothiocyanate electrophiles: chemistry, biochemistry, and pharmacology.

N-Allyl-, N-(cyclopropylmethyl)-, and N-propyl-endo-ethenotetrahydronororipavines (N-substituted 6,14-endo-etheno-4,5-epoxy-3-hydroxy-6-methoxymorphinans) were synthesized with potential acylating or alkylating moieties at the C-7 position (isothiocyanato, (bromoacetyl)amino, and (methoxyfumaroyl)amino) and examined in vivo for their narcotic agonist and antagonist activities and for their ability to interact with opioid receptors in vitro. The N-(cyclopropylmethyl)-substituted compounds were found to have the highest affinity for opioid receptors among these N-substituted compounds, although all of them were found to be reasonably potent narcotic antagonists in the mouse tail flick vs. morphine assay. Their in vivo potency ranged from 1/8 to 4 times that of nalorphine on intravenous injection in mice. Rat brain membrane binding studies indicated that the compounds interacted with opioid receptors with potencies that ranged from 0.5 times that of morphine (8c, 9c, and 10c) to 0.017 that of morphine (8b). Among the compounds studied here, only the previously reported isothiocyanato compound (10c) and (methoxyfumaroyl)amino compound (8c) interacted irreversibly and selectively with mu or delta opioid receptors, respectively, in assays using NG108-15 neuroblastoma-glioma hybrid cells and/or in a rat brain membrane preparation. Both 8c and 10c were found to interact irreversibly, to a limited extent, with kappa opioid sites in rat brain membranes in which the mu and delta opioid receptors were depleted by interaction with the mu-selective irreversible ligand BIT and the delta-selective irreversible ligand FIT. Neither compound showed irreversible actions in the electrically stimulated mouse vas deferens preparation.

Animals↗