Morphinan Series Research Articles

Chromatographically separable rotamers of an unhindered amide.

Surprisingly stable formamide rotamers were encountered in the tetrahydroisoquinoline and morphinan series of alkaloids. We investigated the hindered rotation around the amide bond by dynamic high-performance liquid chromatography (DHPLC) and kinetic measurements of the interconversion of the rotamers which can readily be separated by HPLC as well as TLC. The experimental results of the different methods were compared to each other as well as to results obtained by DFT calculations.

Levorphanol: the forgotten opioid

Levorphanol (levo-3-hydroxy-N-methylmorphinan) is a strong opioid that is the only available opioid agonist of the morphinan series. Levorphanol was originally synthesized as a pharmacological alternative to morphine more than 40 years ago. It is considered a step-3 opioid by the World Health Organization (WHO) and has a greater potency than morphine. Analgesia produced by levorphanol is mediated via its interactions with mu, delta, and kappa opioid receptors. Levorphanol is also an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence that levorphanol may inhibit uptake of norepinephrine and serotonin. Similar to morphine, levorphanol undergoes glucuronidation in the liver, and the glucuronidated products are excreted in the kidney. Levorphanol can be given orally, intravenously, and subcutaneously. This article reviews the pharmacodynamics, pharmacology, and clinical efficacy for this often overlooked step-3 opioid. The long half-life of the drug increases the potential for drug accumulation. Levorphanol has clinical efficacy in neuropathic pain.

Comparison of the Antinociceptive Response to Morphine and Morphine-Like Compounds in Male and Female Sprague-Dawley Rats

Male rats are more sensitive to the antinociceptive effects of morphine than female rats. This difference is seen across several rat strains using a variety of nociceptive stimuli. However, the literature in regard to sex differences in antinociceptive responses to mu-opioids other than morphine is less consistent. The present study was designed to examine whether there is a structure-activity rationale that determines which mu-opioids will show a differential antinociceptive response between male and female rats. A series of morphinans closely related in structure to morphine, namely, codeine, heroin, hydrocodone, hydromorphone, oxymorphone, and oxycodone, were examined for their antinociceptive activity in male and female Sprague-Dawley rats and compared with the structurally unrelated mu-opioid agonists methadone and fentanyl. Antinociception was measured by the warm-water tail-withdrawal assay. The results show that morphine is more potent in males compared with females > hydromorphone = hydrocodone = oxymorphone, but there was no observable sex difference in the antinociceptive potency of codeine, heroin, oxycodone, methadone, or fentanyl. The potency to stimulate guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding and binding affinity of the various morphinans was compared in rat glioma C6 cells expressing the rat mu-opioid receptor; relative efficacy was also compared by stimulation of [35S]GTPgammaS binding in slices of rat brain thalamus. The presence of a sex difference in antinociceptive responsiveness was not related to drug potency, efficacy, or affinity. Consequently, it is likely that differential metabolism of the opioid, possibly by glucuronidation, determines the presence or absence of a sex difference.

Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors.

A novel series of morphinans were synthesized, and their binding affinity at and functional selectivity for micro, delta, and kappa opioid receptors were evaluated. These dimeric ligands can be viewed as dimeric morphinans, which were formed by coupling two identical morphinan pharmacophores (cyclorphan (1) or MCL 101 (2)) with varying connecting spacers. Ligands 6 and 7 with alkyl spacers on the nitrogen position and ligands 8 and 9 in which the two morphinan pharmacophores were coupled by ether moieties at the 3-hydroxyl positions showed significant decrease in affinity at all three opioid receptors. An improvement in the affinity was achieved by introducing an ester moiety as the spacer in the dimeric morphinans. It was observed that the affinity of these ligands was sensitive to the character and length of the spacer. Compound 13 (MCL-139) with a 4-carbon ester spacer, compound 17 (MCL-144) containing a 10-carbon spacer, and compound 19 (MCL-145) with the conformationally constrained fumaryl spacer were the most potent ligands in this series, displaying excellent affinities at micro and kappa receptors (K(i) = 0.09-0.2 nM at micro and K(i) = 0.078-0.049 nM at kappa), which were comparable to the parent compound 2. Ligand 12, a compound containing only one morphinan pharmacophore and a long-chain ester group, had affinity at both micro and kappa receptors almost identical to that of the parent ligand 2. In the [(35)S]GTPgammaS binding assay, ligands 13, 17, and 19 and their parent morphinans 1 and 2 stimulated [(35)S]GTPgammaS binding mediated by the micro and kappa receptors. Compounds 13 and 17 were full kappa agonists and partial micro agonists, while compound 19 was a partial agonist at both micro and kappa receptors. These novel ligands, as well as their interesting pharmacological properties, will serve as the basis for our continuing investigation of the dimeric ligands as potential probes for the pharmacotherapy of cocaine abuse and may also open new avenues for the characterization of opioid receptors.

Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse

Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine (1a) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the morphinan, l-cyclorphan (3a) and the benzomorphan, l-cyclazocine (2). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan 3a–c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b, structurally related to ketocyclazocine (1a). In binding experiments l-cyclorphan (3a), the cyclobutyl (3b), the tetrahydrofurfuryl 3c and the 10-keto 4b analogs had high affinity for mu (μ), delta (δ) and kappa (κ) opioid receptors. Both 3a and 3b were more selective for the κ receptor than the μ receptor. However, 3b was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (3a) had only a 4-fold greater affinity for the κ receptor in comparison to the δ receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds 3a and 3b were κ agonists. Correlating with the binding results, compound 3a had some δ agonist properties, while 3b was devoid of any activity at the δ receptor. In addition, compounds 3a and 3b had opposing properties at the μ opioid receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist.

Unexpected rearrangement involving azide-olefin cycloaddition in morphinan series

Tricyclic azide 3b rearranges into imine 4, instead of the expected morphinan derivative.

Synthesis of the skeleton of the morphine molecule by mammalian liver.

The possibility that morphine could be synthesized in animals has long been considered and a pathway in mammalian brain analogous to that in the opium poppy has been proposed. Substances have been detected in mammalian brain that are recognized by antisera raised against morphine. Recently we reported the presence of three such immunoreactive substances in bovine hypothalamus and adrenal, and in rat brain, and the definitive identification of two of them by gas chromatography-mass spectrometry as morphine and codeine. Incorporation of a labelled precursor has demonstrated the biosynthesis of morphine in the opium poppy from tyrosine-derived units (see Fig. 1). Intramolecular coupling of reticuline to form salutaridine is the critical step that generates the morphine skeleton (morphinan) and the stereochemistry of the morphinan series. We now report the conversion in vivo and in vitro of reticuline to salutaridine by rat liver, but this conversion is not detectable in rat brain and bovine adrenal. This is the first direct demonstration of the synthesis of a morphinan in an animal tissue and also supports the hypothesis that morphine and codeine in brain and adrenal are of endogenous origin.

Studies in the (+)-morphinan series. 7. Unusual crystallographic and tautomeric properties of (+)-4-hydroxy-7-oxo-3-methoxy-17-methyl-5,6-dehydromorphinan: an interlacing double helix

Studies in the (+)-morphinan series. 7. Unusual crystallographic and tautomeric properties of (+)-4-hydroxy-7-oxo-3-methoxy-17-methyl-5,6-dehydromorphinan: an interlacing double helix

Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone

(+)-Naloxone was prepared in 26% overall yield in eight steps from (+)-7-bromodihydrocodeinone dimethyl ketal by a synthesis which excluded enantiomeric contamination. (+)-Naloxone was examined in three assay systems and found to have no more than 1/1000(-1)/10 000th the activity of (-)-naloxone; it can, thus, serve to test the stereospecificity of the biochemical and pharmacological actions of (-)-naloxone.

Studies in the (+)-morphinan series. 4. A markedly improved synthesis of (+)-morphine

Studies in the (+)-morphinan series. 4. A markedly improved synthesis of (+)-morphine

ChemInform Abstract: SYNTHESES OF PENTACYCLIC MORPHINAN ANALOGS

AbstractAusgehend von Verbindungen wie (I), (IV), (VIII) werden Morphinan‐Vorstufen wie (II), (V), (VII) bzw. (IX) synthetisiert, die durch Grewe‐Cyclisierung Morphinane wie (III), (VI) bzw. (X) liefern.

Syntheses of Pentacyclic Morphinan Analogs

The synthesis of a series of morphinans with an additional aromatic or alicyclic ring fused to the 5,6 positions or an alicyclic ring fused to the 16,17 positions is described. The synthetic sequence involved elaboration of a 1,2,3,4,5,6-hexahydrobenz[f]isoquinoline or a quinolizidine, Grewe cyclization to a morphinan, and modification of the functional groups of the morphinan. These morphinans showed poor to moderate analgesic and narcotic antagonist activity.

THE EFFECTS OF MORPHINE AND OTHER NARCOTICS ON THYROID FUNCTION IN MICE

ABSTRACT Several drugs from the morphine, pethidine and morphinan series were evaluated with respect to their action on the pituitary secretion of thyrotrophin (TSH). This action was measured by the release and the uptake of 131I by the thyroid gland of mice. Daily administration of 500 μg of morphine, codeine, dihydromorphinone, levorphan, dextrorphan or meperidine significantly depressed the uptake of 131I by the thyroid gland within five days. Single injections of 500 μg of either dihydromorphinone or levorphan increased the thyroidal uptake of 131I The thyroids of hypophysectomized mice, pretreated with 131I and thyroxine, failed to respond to injections of these drugs. Daily administration of these drugs for five days failed to change pituitary content of TSH from the control level, or to effect a change in the turn-over rate of exogenous radiothyroxine. These results suggest that these drugs do not exert direct action on the thyroid but act on thyroid function through their effect on the hypothalamus-pituitary axis.

Hydroxy‐Morphinane. Mitteilung. Über ein Photooxydationsprodukt von (+)‐3‐Methoxy‐N‐methyl‐morphinan

AbstractPhotooxydation of (+)‐3‐methoxy‐N‐methyl‐morphinan hydrobromide (I, HBr, Romilar Roche) yields (−)‐3‐methoxy‐10‐oxo‐N‐methyl‐morphinan (II). The structure of the compound has been established. The introduction of a carbonyl group in position 10 is easily achieved in good yield also by oxydation with chromic acid. Whereas reduction of the 10‐oxo‐compound with lithium aluminium hydride leaves the tetracyclic ring structure of the morphinan compound unchanged, reduction according to Clemmensen causes scission of the ring, leading to a tricyclic octahydro‐phenanthrene with angular basic side chain, the structure of which has been established by synthesis. Pharmacological tests revealed that the introduction of a carbonyl or hydroxy group in position 10 of the dextro series of morphinans causes a marked decrease in the antitussive activity. The corresponding derivatives of the Zaevo series have almost entirely lost their analgesic activity.

Cardiovascular and central nervous system effects of morphinan series.

SummaryThe effects of 5 members of the morphinan series have been studied on the electroencephalogram, electrocardiogram and blood pressure of the dog. Levorphan produced maximum central effects with mild cardiovascular depression. Dextrorphan produced severe cardiovascular depression with little or no direct central effect. Levomethorphan and dextromethorphan had mild central and peripheral actions. Levallorphan, which had little action by itself, antagonized both the central and peripheral effects of levorphan.

Evaluation of a new antitussive agent.

DEXTRO-3-methoxy-N-methylmorphinan§ hydrobromide (dextromethorphan hydrobromide) is an experimental drug that has shown cough-inhibiting properties in animals, but the degree of this effect in human beings was not known. Therefore, a study was undertaken to determine the antitussive effect of this substance clinically. The merits of another compound of the morphinan series, racemic-3-hydroxy-N-methylmorphinan hydrobromide, as a potent analgesic agent are well known.1 2 3 4 5 6 After the resolution of the racemate into its optically active isomers by Schnider and Grussner,7 pharmacologic studies by Randall and Lehmann,8 Fromherz9 and Benson et al.10 showed that the analgesic action of racemorphan resides in its levorotatory component. Similarly, Isbell . . .