Phenolic analogues of diastereoisomeric 2-methyl reversed esters of pethidine

Casy, A. F.; Dewar, George H.; Pascoe, R A

doi:10.1111/j.2042-7158.1989.tb06434.x

Cited by 7 publications

(3 citation statements)

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“…All the tropanes failed to block the antinociceptive actions of morphine in the tail-flick test (Harris & Pierson 1964). Hendershot & Forsaith (1959). phenol IOd (Ar = rn-methoxyphenyl), in the TF assay (1.6 times that of 3) may be attributed to the well-known advantageous effect of replacing N-methyl by N-phenethyl in many classes of opioid (Janssen & Eddy 1960;Casy & Parfitt 1986). The N-ally1 congener IOb (Ar = rn-OHC6H4) failed to antagonize morphine in the TF test (as did all other tropanes examined) and behaved as a weak agonist in the PPQ procedure (one-fifteenth as potent as 3).…”

Section: Pharmacology Results and Discussionmentioning

confidence: 99%

“…The antinociceptive potencies of these compounds in mice are reported, and discussed in relation to non-phenolic congeners and the 4-arylpiperidine moiety of morphine. This paper reports the synthesis and pharmacological evaluation of some tropane analogues of pethidine to study the influence of rn-hydroxylation on opioid ligands of the 4-arylpiperidine class which show preference for axial-aryl chair conformations ( I ) (Casy 1989;Casy et al 1989). to give the free phenol (9) and N-demethylated with 2,2,2-trichloroethylchlcroformate to give the sec-amine 10a(Ar = m-hydroxyphenyl).…”

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confidence: 99%

“…This paper reports the synthesis and pharmacological evaluation of some tropane analogues of pethidine to study the influence of rn-hydroxylation on opioid ligands of the 4arylpiperidine class which show preference for axial-aryl chair conformations ( I ) (Casy 1989;Casy et al 1989). Bell & Archer (1960) described the conversion of 3-tropanone (2) to the a-phenyltropane analogue of pethidine (3) by a multistep route which was subsequently re-investigated with provision of spectroscopic evidence of stereochemistry (Casy & Coates 1974).…”

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Opioid Properties of Some Derivatives of Pethidine Based on Tropane

Casy

Dewar

Pascoe

1992

Journal of Pharmacy and Pharmacology

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The preparation of some tropane analogues of pethidine and its reversed ester, chiefly with preferred 3 alpha-m-hydroxyphenyl chair conformations, is described. The former were secured from tropan-3-one in a sequence of reactions involving cyanide attack, hydrolysis, Grignard attack and then rearrangements. The reversed ester was obtained by treating tropan-3-one with lithium phenyl, followed by acylation. Configurational and conformational assignments follow from NMR analysis. The antinociceptive potencies of these compounds in mice are reported, and discussed in relation to non-phenolic congeners and the 4-arylpiperidine moiety of morphine.

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Section: Pharmacology Results and Discussionmentioning

confidence: 99%

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Opioid Properties of Some Derivatives of Pethidine Based on Tropane

Casy

Dewar

Pascoe

1992

Journal of Pharmacy and Pharmacology

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Narcotic Analgesics

Aldrich

Vigil‐Cruz

2003

Burger's Medicinal Chemistry and Drug Discovery

147

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Narcotic analgesics such as morphine have been the mainstay for the treatment of severe pain, although these drugs are associated with serious adverse effects, most notably addiction liability and respiratory depression. Therefore there has been an intensive effort to find new therapeutic agents that retain the effectiveness of morphine, but do not have its undesired side effects. Compounds have been identified from a wide variety of chemical classes, from the rigid morphinan alkaloids to the flexible phenylpiperidines and the opioid peptides, which have affinity for opioid receptors. In recent years considerable effort has focused on identifying ligands, both agonists and antagonists, with affinity for delta (δ) and kappa (κ) opioid receptors as pharmacological tools and as potential therapeutic agents that would not have the side‐effect profile of morphine and other agonists that interact with mu (μ) opioid receptors. After the identification of the closely related opioid receptor‐like (ORL1) receptor and its endogenous ligand orphanin FQ/nociceptin, there has been considerable effort directed toward identifying agonists and antagonists for this receptor as well. This review discusses the structure‐activity relationships for each of the major classes of compounds that interact with the opioid receptors, along with ligands for the ORL1 receptors.

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Opioid Receptor Ligands

McCurdy

Prisinzano

2010

Burger's Medicinal Chemistry and Drug Discovery

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Opioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.

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Phenolic analogues of diastereoisomeric 2-methyl reversed esters of pethidine

Cited by 7 publications

References 11 publications

Opioid Properties of Some Derivatives of Pethidine Based on Tropane

Opioid Properties of Some Derivatives of Pethidine Based on Tropane

Narcotic Analgesics

Opioid Receptor Ligands

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