George H. Dewar

Analysis of cocaine, benzoylecgonine, ecgonine methyl ester, ethylcocaine and norcocaine in human urine using HPLC with post-column ion-pair extraction and fluorescence detection

The measurement of cocaine and its major metabolites has been achieved by an HPLC method that compensates for their different solubilities and detection properties. Although ecgonine methyl ester is a major metabolite it is generally not measured by HPLC because it is poorly detectable by UV, and its water solubility makes recovery from urine difficult. Using modified solid-phase extraction procedures recoveries of 85% for ecgonine methyl ester, 97% for cocaine, 106% for benzoylecgonine and 80% for ethylcocaine have been obtained from urine. Increased chromatographic retention and detection sensitivity has been obtained by formation of the t-butyldimethylsilyl derivative of ecgonine methyl ester which was found to be stable in the HPLC mobile phase for at least 1 week. Alkylation of norcocaine and benzoylecgonine has improved their detection sensitivity and also chromatographic resolution. All calibrations were linear over the range 200-1000 ng ml-1 in urine with correlation coefficients > 0.99.

The effects of novel vasodilator long chain acyl carnitine esters in the isolated perfused heart of the rat.

1 The effects of palmitoyl carnitine (PC) and novel derivatives were examined on the isolated Langendorff perfused heart of the rat. 2 Bolus injections of PC (1–300 nmol) produced coronary constriction accompanied by a cumulative irreversible depression of contractility. 3 Prior storage of PC in chloroform containing 2% ethanol in heat‐sealed ampoules resulted in production of the ethyl ester of the compound (PCE). This compound was isolated and also synthesized (P1E). In contrast to PC, both PCE and P1E exhibited potent vasodilator activity. 4 Increasing the fatty acid chain length from palmitoyl to stearoyl resulted in a significant reduction in coronary dilator activity of the ester compound, whereas different ester groups did not affect the vasodilator action appreciably. Complete removal of the fatty acid chain abolished all vascular effects at the doses used. 5 The vasodilatation produced by these acyl carnitine esters was comparable to that produced by several known vasodilator drugs including verapamil, cromakalim, amyl nitrate and iloprost; however, the duration of the vasodilator response was more prolonged with the carnitate derivatives.

Captopril and its probable contaminants: NMR and MS features of analytical value.

The 400 MHz 1H NMR spectrum of captopril in a variety of solvents is analysed and compared with those of epicaptopril and its disulphide analogue. A method for detecting isomeric and oxidative impurities by examination of a 1H NMR spectrum of captopril in DMSO-d6 is proposed. 13C NMR and MS data enable differentiation of captopril from its disulphide analogue but not from its diastereoisomer epicaptopril.

Nomenclature and Methodology

It is assumed that most readers of this book will already be familiar with stereochemical principles and will have knowledge of pharmacological concepts and methods. Nevertheless, a summary of basic principles of these kinds is held to form an appropriate and useful starting point for the main topic of the book. The purpose of this summary is to serve as an “aide-memoire,” to update prior knowledge, and to direct attention to stereochemical aspects which recur throughout the main text. Material presented relates, on the one hand, to the molecular geometry of organic structures and, on the other, to pharmacological methodology.

Opioid Properties of Some Derivatives of Pethidine Based on Tropane

Abstract— The preparation of some tropane analogues of pethidine and its reversed ester, chiefly with preferred 3α‐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.

The Synthesis, and Structure-activity Relationships of some Long Chain Acyl Carnitine Esters on the Coronary Circulation of the Rat Isolated Heart

Abstract— The synthesis of the isopropyl ester of carnitine and a series of fatty acid derivatives with fatty acid lengths C8‐C30 is described. Bolus doses of these compounds (0·03–300 nmol) showed coronary vasodilator activity in the rat isolated heart. Increasing fatty acid chain length from C8 to C16 resulted in an increased vasodilator potency. Longer lasting vasodilation was observed with the C20 compound. Increasing fatty acid chain length to C30 was associated with a small dilator response preceded by vasoconstriction.

Conformational equilibra of hydrochloride salts of pethidine, ketobemidone, and related central analgesics of the 4-arylpiperidine class

The n.m.r. (1H, 13C) spectra of hydrochloride salts of pethidine, ketobemidone, 4-m-hydroxyphenyl-1,4-dimethylpiperidine, and the reversed ester of pethidine and its analogues are reported. Analysis of the data shows that, apart from the reversed esters, both N-protonated epimers are significantly populated when the salts are dissolved in D2O. The equatorial 4-aryl chair conformer is the major epimer of pethidine and ketobemidone, but the minor form in the case of the 1,4-dimethyl derivative. Little evidence for axial 4-aryl chair epimers has been found for solutes of the reversed esters of pethidine. The results corroborate previous computational studies, and are discussed in terms of differing binding modes of the two classes of 4-arylpiperidine ligand at opioid receptors.

Phenolic analogues of diastereoisomeric 2-methyl reversed esters of pethidine

Abstract— The preparation and stereochemical characterization of α‐ and β‐isomers of 1,2‐dimethyl‐4–m‐hydroxyphenyl‐4‐propiony‐loxypiperidine are described. Both the α (axial 4‐aryl/chair) and β (equatorial 4‐aryl/chair) isomers were of low potency or inactive in mice antinociceptive tests. Shortcomings of the α‐isomer as a model for the 4‐arylpiperidine moiety of morphine are discussed.

Vasodilator action of the isopropyl ester of palmitoyl carnitine in the rat coronary circulation and mesenteric vascular bed

The vasodilator action of the isopropyl ester of palmitoyl carnitine (P1Pi) has been examined in perfused rat hearts and mesenteric vessels. The coronary vasodilator effect P1Pi was not significantly inhibited by flurbiprofen (10 microM), BW755C (10 microM), glibenclamide (10 microM) or the bradykinin B2 receptor antagonist D-Arg0[Hyp3,Thi5,8,D-Phe7]bradykinin (1 microM), indicating that the action of P1Pi is not mediated via arachidonic acid metabolites, ATP-dependent K+ channels or bradykinin B2 receptors. L-NG-Nitro arginine (100 microM) did not inhibit the vasodilator action of P1Pi whilst superoxide dismutase (20 and 50 U.ml-1) attenuated its vasodilator action. Methylene blue (10 microM) caused inhibition in three out of four hearts, while haemoglobin (1 microM) caused an irreversible inhibition of the action of P1Pi which was associated with a depression of myocardial contractility. In air-damaged mesenteric vascular beds the vasodilator action of P1Pi was not attenuated, whilst that of acetylcholine was abolished. In K(+)-depolarised mesenteric vascular beds the constrictor action of Ca2+ was attenuated by P1Pi. Therefore the vasodilator effect of P1Pi appears to be the result of a direct effect on smooth muscle.

Opioid Properties of Some Isomeric Derivatives of Phencyclidine

Abstract— The phencyclidine analogues (±)‐α‐, (±)‐β‐, and (+)‐α‐ and (–)‐α‐4‐hydroxy‐3‐methyl‐4‐phenyl‐l‐(1‐phenylcyclohexyl)piperidine, all with known relative and absolute stereochemistry, have been prepared, and their analgesic potencies related to corresponding prodines. In contrast to the prodines, the (±)‐α‐phencyclidine analogue was a more potent analgesic than its diastereoisomer, while in agreement with observations in the prodine series, the 3R, 4S‐α‐enantiomer displayed substantially greater potency than its mirror image form.