O. William Lever

Increased biological activity of dimers of oxymorphone and enkephalin: Possible role of receptor crosslinking

Abstract Four analogs of oxymorphone, oxymorphaminoethylthiol, oxymorphamino-ethyldisulfide, oxymorphaminoethyl-nitrobenzoic acid disulfide and oxymorphone thiazolidine, as well as the enkephalin analogs, enkephalin-thiol, Tyr-D-Ala-Gly-Phe-Leu-Lys(ϵ-NH)COCH 2 CH 2 SH and the enkephalin-dimer, [Tyr-D-Ala-Gly-Phe-Leu-Lys(ϵ-NH)COCH 2 CH 2 S-] 2 , were examined for binding to enkephalin and morphine receptors. The analogs gained substantial affinity for enkephalin and lost affinity for morphine receptors. The affinity of the dimers of both opiates and enkephalins was slightly greater than that achieved by the corresponding thiol monomers. However, in the guinea pig ileum the dimeric analogs were much more active than the monomers. Receptor dimerization or cross-linking may be involved in the biological activity of opiates and opioid peptides.

Preparation of α-oxygenated phosphine oxides from chlorodiphenylphosphine

Abstract A range of α-alkoxyphosphine oxides, including novel α-methoxyallyl oxides, are readily prepared from chlorodiphenylphosphine and acetals.

Regiochemistry of reactions of α-alkoxyallylphosphine oxide ylides with electrophiles.

Abstract Anions 4 , derived from α-methoxyallylphosphine oxides 3 , react with electrophiles in a highly regioselective fashion to give products of α-attack or γ-attack depending upon the substitution pattern of the ylid 4 and the nature of the electrophile.

Solution conformations of the 6α and 6β epimers of oxymorphamine

Abstract High field (360 MHz) 1 H NMR studies have shown that the conformation of ring C in the oxymorphamines is dramatically influenced by the stereochemistry of the 6-amino group: ring C exists in a chair conformation in the 6β-epimer but adopts a twist boat conformation in the 6α-epimer.

Oxazolo[4, 5-b]pyridines. Regioselective metalation of the 2-diethylaminooxazolo[4, 5-b]pyridine system and formation of 7-substituted derivatives

Metalation of 2-diethylaminooxazolo[4, 5-b]pyridine with tert-butyllithium occurs regioselectively in the 7-position of the heterocycle and the fused 2-dialkylaminooxazolo group thus functions as an ortho-directing group in the bicyclic system. Reaction of the resulting 7-lithio intermediate with electrophiles provides access to a variety of 7-substituted derivatives.

Synthesis of a Novel Oxazolo[4,5-f][1,6]naphthyridine

Abstract 7-Azo-2-diethylaminooxazolo-[4,5-b]pyridine (1) is converted in 5 steps to the novel oxazolo[4,5-f][1,6]naphthyridine-6-oxo-7-carboxylic acid 6.

Chapter 6. Analgesics, Opioids, and Opioid Receptors

Publisher Summary The search for superior analgesics with improved side-effect profiles continues in the clinic through additional evaluations of nonsteroidal anti-inflammatory peripheral analgesics and through continued study of oral administration of centrally acting analgesics. Non-steroidal anti-inflammatory drugs (NSAIDs) evaluated as oral analgesics for postoperative pain includes: fenoprofen, etodolac, isoxepac, zomepirac, and diflunisal. For relief of pain following outpatient surgery, oral fenoprofen (200 mg) compares favorably with parenteral morphine (8 mg) after an initial two hour period during that morphine is more effective. Diflunisal (dolobid) appears to be a well-tolerated NSAID. Diflunisal is an efficacious and long-acting (up to 12 hours) analgesic for oral surgery patients and is effective against pain encountered in general practice. In the treatment of chronic back pain, diflunisal (500 mg twice daily) appears superior to paracetamol (1000 mg four times a day) although less effective than naproxen sodium (550 mg twice a day). Studies with diflunisal, flurbiprofen, ibuprofen, naproxen sodium, and zomepirac sodium provide additional evidence of the effectiveness of oral NSAIDs for the treatment of the symptoms of primary dysmenorrhea. In the treatment of renal colic, intramuscular injection of the NSAID diclofenac (50 mg) is more effective than the injection of a narcotic–spasmolytic combination drug.

Oxazolo[4,5-b]pyridines. Regiochemistry of Electrophilic Substitution in the 2-Diethylaminooxazolo[4,5-b]pyridine System: Synthesis of 6-Substituted Derivatives

Abstract Electrophilic substitution occurs regiospecifically at C-6 in the 2-diethylaminooxazolo-[4,5-b]pyridine system to provide 6-nitro and 6-halo derivatives. The 6-nitro compound is readily converted to the 6-amino derivative which may be further elaborated by standard methods to provide more complex derivatives.

Synthesis of Isoquinolines Bearing Differentially Functionalized Nitrogen Substituents at Positions 3 and 4 through Amine Displacement on a 4-Nitro-3-(p-toluenesulfonyloxy)isoquinoline

Abstract A method for the synthesis of isoquinolines functionalized with differentiated nitrogen substituents at positions 3 and 4 is described. The method involves tosylarion of a 3-hydroxy-4-nitroisoquinoline and subsequent tosylate displacement by amine nucleophiles to give 3-amino-4-nitroisoquinolinc derivatives, the products of specific C-O bond cleavage. Reduction of the 4-nitro group and elaboration of the resulting 4-amino moiety provides the differentiated 3- and 4-amino functions, not readily available by other methods. Appropriately substituted compounds are amenable to further transformations, illustrated by their conversion to imidazo[5,4-c]isoquinoline derivatives. Additional studies on the tosylatc displacement indicated that thiol displacement also occurs by scission of. the CO bood to give a 3-thioether derivative, and that reactions of the 4-nitro-3-tosyloxyisoquinoline system with certain other nuclcophilcs, including alcohols, did not proceed readily.

Chapter 1. Analgesics

Publisher Summary This chapter discusses the progress in opioid and nonopioid analgesia along with selected clinical highlights. Opioid peptide biosynzhesis was summarized previously and additional overviews of the biosynthesis and distribution of endogeneous opioids have appeared. Several inhibitors of enkephalin convertase, a carboxypeptidase that may liberate enkephalins from immediate precursors, are described in the chapter. Thiorphan was reported to reduce postmyelographic side effects when administered to patients prior to myelography. Oral administration of D-phenylalanine, a carboxypeptidase inhibitor, was found to be of benefit in patients with certain chronic pain complaints; the drug was most effective after 3 - 5 weeks of therapy. The number of endogenous opioid peptides continues to grow rapidly. Several fragments of proenkephalin A have received recent attention. A μ-selective octapeptide fragment has been designated both as metorphamide and as adrenorphin. Several studies indicate that opioids acti ate erotonergic neurons and increase 5-HT turnover in the spinal cord. Intrathecal 5-HT produced anti-nociception in mice. The role of serotonergic neurons in opioid analgesia may be modek-dependent. Central cholinergic fibers may also mediate analgesia, and both musscarinic and nicotinic agonists produce analgesia in rodents by central mechanisms. There is evidence that cholinergic connections mediate the expression of both endogenous and exogenous opioid analgesia. The analgesic properties of cannabinoid derivatives are well known, though no such drugs have yet been demonstrated to be substantially free from the CNS side effect to which Cannabis sativa owes its popularity as a substance of abuse. Discussion on several clinical highlights of various analgesics has enriched the content of the chapter to a great extent.