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.

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.

Optical purity determination by NMR: use of chiral lanthanide shift reagents and a base line technique.

A method for optical purity determination of a range of chiral drug molecules by NMR spectroscopy is reported. This technique involves the use of optically active lanthanide shift reagents and a newly developed base line analysis. Its applicability was demonstrated for a variety of drugs including nonsteroidal antiinflammatory agents and some adrenergic agents. It is established that successful application of the method depends on a constant shift reagent to sample molar ratio, constant instrumental conditions for all solutions, and the use of a calibration curve derived from solutions containing the same total concentration of the two enantiomers. For the examples cited, the correlation coefficient is not less than 0.97, and a mathematical treatment is included which supports the basis of the method.

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.

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.

Phenolic analogues of diastereoisomeric 2-methyl reversed esters of pethidine.

The preparation and stereochemical characterization of alpha- and beta-isomers of 1,2-dimethyl-4-m-hydroxyphenyl-4-propionyloxypiperidine are described. Both the alpha (axial 4-aryl/chair) and beta (equatorial 4-aryl/chair) isomers were of low potency or inactive in mice antinociceptive tests. Shortcomings of the alpha-isomer as a model for the 4-arylpiperidine moiety of morphine are discussed.

Structure-activity relationships of some novel coronary dilator derivatives of palmitoyl carnitine in the rat isolated heart.

The structure-activity relationships of some novel coronary dilator derivatives of palmitoyl carnitine in the rat isolated perfused heart are described. It has been shown previously that esterification of palmitoyl carnitine changes the activity of the compound from a coronary constrictor to a coronary dilator. In this study, it was found that the ester group is not a necessary requirement for coronary dilator activity, but only the absence of the negatively charged carboxylic acid group of palmitoyl carnitine, as compounds containing an ethyl group in place of the ester group were also active coronary dilators. Furthermore, substituting the methyl groups attached to the nitrogen atom of the molecule profoundly altered coronary dilator activity. A quaternary ammonium group was a necessary requirement for potent coronary dilator activity.

Opioid properties of some derivatives of pethidine based on tropane.

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.

Opioid properties of some isomeric derivatives of phencyclidine.

The phencyclidine analogues (+/-)-alpha-, (+/-)-beta-, and (+)-alpha- and and (-)-alpha-4-hydroxy-3-methyl-4-phenyl-1-(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 (+/-)-alpha-phencyclidine analogue was a more potent analgesic than its diastereoisomer, while in agreement with observations in the prodine series, the 3R,4S-alpha-enantiomer displayed substantially greater potency than its mirror image form.

The synthesis, and structure-activity relationships of some long chain acyl carnitine esters on the coronary circulation of the rat isolated heart.

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.

Stereochemical influences upon the opioid ligand activities of 4-alkyl-4-arylpiperidine derivatives.

The synthesis and stereochemistry (configuration and preferred solute conformation) of some 4-alkyl (methyl, n-propyl, isobutyl)-4-(3-hydroxy-phenyl)-1-methylpiperidines and corresponding 3-methyl diastereoisomeric pairs are reported, together with their in vivo and in vitro activities as opioid ligands. All potent agonists exhibit a preference for axial 4-aryl chair conformations when protonated, and stereochemical analogies with rigid opioids of the benzomorphan class are discussed. Antagonist properties are found in compounds with preference for equatorial 4-aryl chairs, notably the cis 3,4-dimethyl derivative.

Effect of palmitoyl carnitine isopropyl ester on the actions of BAY K 8644 and norepinephrine in the perfused rat heart.

We examined the actions of the isopropyl ester of palmitoyl carnitine (P1Pi), a novel vasodilator compound, on coronary constriction mediated by the calcium channel activator BAY K 8644 and positive inotropic responses mediated by norepinephrine (NE) and low sodium perfusion in perfused rat hearts. Langendorff-perfused hearts were given bolus doses of BAY K 8644 or NE. The effects of P1Pi or atenolol on perfusion pressure, heart rate (HR), and developed tension changes induced by these agents were studied. In other experiments, low-sodium perfusion was used to manipulate sodium-calcium exchange in the presence and absence of P1Pi. P1Pi inhibited the coronary constrictor action of BAY K 8644 and also produced a selective inhibition of the inotropic but not the chronotropic action of NE. These effects of P1Pi were not associated with any depression of basal myocardial contractility. P1Pi did not affect the inotropic or coronary constrictor responses induced by low-sodium perfusion. The effects of P1Pi on the responses induced by BAY K 8644 and NE indicate that P1Pi inhibits activated L-type calcium channels while having no effect on sodium-calcium exchange. These effects may be related to the charged nature of this amphiphilic compound.

Atracurium: conception and inception.

The rationale underlying the design of atracurium, a bis-quaternary ammonium neuromuscular blocking agent which incorporates the Hofmann elimination as a novel biodegradation pathway, is described. Destruction in vivo, of the bis-quaternary structure essential for neuromuscular blocking activity, by the combination of Hofmann elimination and a parallel ester hydrolysis leads to innocuous breakdown products that are without neuromuscular or cardiovascular effects and to a time-course of action which is unaffected by the level of plasma esterase activity, renal or hepatic function.

A preliminary assessment of atracurium, a new competitive neuromuscular blocking agent.

Atracurium besylate, 2,2'-(3,11-dioxo-4,10-dioxatridecylene)-bis-[6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl 1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate is a potent non-depolarising (competitive) neuromuscular blocking agent in the cat, monkey, dog and anaesthetized man. In man, it caused complete paralysis of the tetanic response of the adductor pollicis muscles at doses of 0.2 mg/kg. Blockade was of medium duration with rapid spontaneous recovery, and was readily reversed by neostigmine. The electrocardiogram, heart rate, arterial blood pressure and central venous pressure were virtually unchanged following doses of 0.2-0.4 mg/kg. Intubation was readily accomplished in 1.5-2 min after administration of 0.25-0.3 mg/kg.