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Biomedical subjects

S E Smits

Publications and source records attributed to S E Smits.

18 recordsLinked to original sources
PubMed1985

Picenadol.

Picenadol is a unique opioid mixed agonist-antagonist analgesic currently under clinical evaluation. Structurally, picenadol is a 4-phenylpiperidine derivative and a racemic mixture whose mixed agonist-antagonist properties are a consequence of the d-isomer being a potent opiate agonist, whereas the l-isomer is an opioid antagonist. In the mouse writhing and rat tail heat tests, the analgesic potency of picenadol is estimated to be 1/3 that of morphine. Picenadol itself has weak antagonist activity, whereas the antagonist potency of the l-isomer is approx. 1/10 that of nalorphine. Evaluation of picenadol's affinity for opioid receptors reveals that picenadol, unlike other mixed agonist-antagonists has high affinity for both the mu and delta receptors but a markedly lower affinity for the kappa receptor. Extensive pharmacological investigations show picenadol to have a low potential to produce opiate-like side effects, including a low liability for abuse and physical dependence.

Animals↗
PubMed1977

Synthesis of two metabolites of (+)-propoxyphene.

Two minor metabolites of (+)-propoxyphene were prepared in both the (+/-) and (+) forms. The optically pure forms were synthesized by a degradative route from (+)-propoxyphene. The di-N-demethylated metabolite 10a,b had weak analgesic activity while the cyclized oxazine metabolite 7a was inactive.

Analgesics↗
PubMed1977

Propoxyphene and norpropoxyphene: pharmacologic and toxic effects in animals.

alpha-d-Propoxyphene and its principle metabolite, alpha-d-norpropoxyphene, were compared pharmacologically to establish their relative opioid profiles as defined by naloxone reversal. Propoxyphene exhibited opioid activity in the following tests: mouse abdominal constriction and rat tail heat analgesic tests, inhibition of the twitch of the guinea-pig ileum and acute lethality in rodents. Norpropoxyphene also showed opioid activity in the rat tail heat and guinea-pig ileum tests, but exhibited nonopioid activity in the mouse abdominal constriction and acute toxicity studies. Jumping in mice, precipitated by naloxone, suggests the following order for liability to produce physical dependence after repeated administration: morphine greater than codeine greater than propoxyphene greater than norpropoxyphene approximately saline. Propoxyphene and norpropoxyphene depressed axonal conduction in isolated peripheral nerve and were comparable in potency to standard local anesthetic agents. The nonopioid actions of norpropoxyphene might be due in part to its local anesthetic properties.

Analgesics, Opioid↗
PubMed1976

Antagonism by naloxone of morphine-induced single-dose dependence and antinociception in mice.

Single-dose physical dependence on morphine, as indicated by the mouse withdrawal jumping test, was reduced in a dose-related fashion by co-administration of naloxone. In the same dose range, naloxone also antagonized the antinociceptive effect of morphine in the mouse writhing test. Dose-response data revealed essentially the same ED50's for naloxone in both tests. These results indicate that naloxone does indeed block the development of morphine-induced single-dose physical dependence in mice and that it does so as effectively as it blocks morphine-induced inhibition of writhing.

Analgesics, Opioid↗
PubMed1976

The binding of the optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives to the opiate receptors of rat brain.

The optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives have been systematically studied for their effects on the binding of 3H-dihydromorphine (3H-DHM) and 3H-naloxone (3H-NLX) to opiate receptors in rat brain homogenate. The relative affinities of these agents in competing for both 3H-DHM and 3H-NLX binding parallel their analgesic effects. 1-Methadone is about 30 times as effective as d-methadone in competing for both 3H-DHM and 3H-NLX binding sites. The reduction of 1-methadone to alpha-d-methadol and subsequent N-demethylation to alpha-d-normethadol reduce its effectiveness as indicated by the increase in the IC50 values for both 3H-DHM and 3H-NLX binding. The reduction of d-methadone followed by N-demethylation produces a potent derivative, alpha-1-normethadol, which has IC50 values on 3H-DHM and 3H-NLX binding similar to those of 1-methadone. The affinity of alpha-1-acetyl-methadol on the binding of both 3H-ligands falls between those of 1-methadone and d-methadone, and increases as it is N-demethylated. alpha-d-Acetyl-methadol is more effective than alpha-1-acetylmethadol in competing for both 3H-ligands from the opiate receptors, and its affinity, unlike that of alpha-1-acetylmethadol, decreases when it is N-demethylated. The affinities of the methadone isomers and related compounds on the binding of 3H-NLX fall in the presence of Na+. The latter property indicates the agonistic nature of this series of druges.

Animals↗
PubMed1975

Quantitation of physical dependence in mice by naloxone-precipitated jumping after a single dose of morphine.

Jumping behavior in mice was precipitated by naloxone after single doses of morphine. The time-effect curves showed that this jumping behavior was delayed compared to the ability of morphine to inhibit writhing and to increase locomotor activity. This dissociation suggests that the jumping response is a true measure of physical dependence rather than the result of a stimulant effect of morphine in the presence of naloxone. The minimum dose of morphine needed to initiate measurable physical dependence fell within the analgesic range. With a constant dose of morphine, the frequency of jumping was directly related to the dose of naloxone employed. The ability to follow the initiation of physical dependence might be useful in conjunction with receptor and neurohumoral studies to uncover the basic mechanisms involved.

Animals↗
PubMed1970

Quantitative studies on the antagonism by naloxone of some narcotic and narcotic-antagonist analgesics.

1. Naloxone was used to study the antagonism of the analgesic effects of some narcotics (morphine sulphate, levorphanol tartrate, and methadone hydrochloride) and narcotic antagonists (pentazocine, cyclazocine, and nalorphine hydrochloride). The analgesic assay used was the mouse phenylbenzoquinone stretching test.2. The in vivo equivalent of a pA(2) value (apparent pA(2)) for naloxone was determined with each agonist. These values were found to be significantly larger with the narcotics than with the narcotic antagonists.3. The slopes in the apparent pA(2) plots were also found to be significantly different. It was concluded that this difference in slopes was probably not due to a lack of equilibrium in one of the two groups of analgesics.4. The results suggest that the narcotic and the narcotic-antagonist analgesics may inhibit stretching in this assay by interacting either with two different receptors or with the same receptor in a different manner.

Animals↗
PubMed1970

Studies on the receptors involved in the action of the various agents in the phenylbenzoquinone analgesic assay in mice.

1. Tolerance to the activity of several narcotic analgesics (morphine, levorphanol, and methadone) and several narcotic-antagonist analgesics (pentazocine, cyclazocine, and nalorphine) was studied in the mouse phenylbenzoquinone stretching test. Virtually complete tolerance was induced by chronic treatment with each of the narcotic agents, while no apparent tolerance was induced by the narcotic antagonists.2. In morphine-tolerant mice there was a high degree of cross-tolerance to the effects of not only the other narcotic drugs but also to those of the narcotic antagonists, acetylsalicylic acid, and physostigmine.3. The effects of morphine and pentazocine were antagonized by naloxone but not by atropine, while the effects of physostigmine were antagonized by atropine but not by naloxone. Neither atropine nor naloxone antagonized the effect of acetylsalicylic acid.4. The results of the tolerance study suggest that there is a fundamental difference in the consequences of receptor interaction for the narcotic and the narcotic-antagonist analgesics. Morphine-tolerant mice exhibit cross-tolerance non-specifically. The selectivity of naloxone and atropine differentiates the narcotic and narcotic-analgesics from the other two agents used in this analgesic test.

Analgesics↗