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.

8-Hydroxypenillic acid: NMR characteristics and facile formation from 6-aminopenicillanic acid.

High field NMR (1H and 13C) spectral characteristics in D2O of 8-hydroxypenillic acid and 6-aminopenicillanic acid (6-APA)-sodium bicarbonate mixtures are reported. The ready conversion of 6-APA to 8-hydroxypenillic acid is demonstrated.

Rapid identification of ergot derivatives by 1H-NMR spectroscopy.

The 400 MHz 1H-NMR spectra of some therapeutically important ergot derivatives (three bases, four protonated bases and four dihydroergoline salts) are analysed in terms of the low field chemical shift region (above 5 ppm), common resonances of rings C and D (below 5 ppm) and C-8 substituent features. Attention is drawn to data of specific analytical value, and a scheme for the rapid identification of members of this group of ergots proposed. Features which provide evidence of the solute conformation of ring D, and isomerization to less active C-8 epimers are also emphasized.

Mass spectrometry as an aid to the identification of ergots and dihydroergots: comparison of hard and soft ionization techniques.

An analysis of the 70 eV electron impact (EI) and fast atom bombardment (FAB) mass spectral features of a variety of ergoline and dihydroergoline derivatives of therapeutic importance is presented with emphasis upon analytical utility. Derivatives which carry non-peptide based C-8 substituents are fully characterized by EI-MS through provision of molecular wieght evidence and fragment ions diagnostic of both the ergoline skeleton and the C-8 substituent. Peptidic ergolines and dihydroergolines are poorly characterized by EI-MS, but their FAB-MS clearly reveal [M + 1]+ (high intensity) and [M - 1]- (high to low intensity) ions in positive and negative ion spectra, respectively. Negative FAB spectra of salts also display diagnostic anion-base conjugate ions.

Molecular mechanism of delta-selectivity of indole analogs of nonpeptide opioids.

A combined experimental and computational approach was used to understand the mechanism of delta-receptor selectivity of a series of nonpeptide opioids. Six pairs of fused ring opioids/indole derivatives were studied. Receptor-binding assays using [3H][D-Ala2-MePhe4-Gly-ol]-enkephalin (mu), [3H][D-Pen2-D-Pen5]-enkephalin (delta), and [3H]U-69593 (kappa) were performed in guinea pig whole-brain membranes. Agonist activity was determined in norbinaltorphimine- or beta-funaltrexamine-treated guinea pig ileum (mu and kappa) and beta-funaltrexamine-treated mouse vas deferens (delta). Steric and electronic properties were calculated for each compound. Although the parent compounds were selective for the mu-receptor, the indole analogs displayed selectivity for the delta-site because of a decrease in mu-affinity accompanied by an increase in delta-affinity. The indole analogs displayed little or no activity at the delta-receptor. The role of the indole in enhanced delta-recognition is likely interaction with a lipophilic site in the receptor. The diminished mu-affinity of the indole analogs is a result of the loss of the carbonyl oxygen as the proton-accepting center, which we have previously determined to be important for recognition of the mu-receptor.

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.

Analogues of triprolidine: structural influences upon antihistamine activity.

The synthesis of some geometrical isomers related to triprolidine is reported. Previous configurational assignments, by UV and proton NMR, are validated by high field nuclear Overhauser enhancement methods and the isomeric purity of tested E- and Z-isomers was greater than 99.5% as assessed by an HPLC method developed for these compounds. Affinity constants for triprolidine (E and Z) in guinea-pig ileum showed a potency ratio of approximately 600 whereas at cerebellar sites this ratio was only approximately 100, suggesting that the H1 receptor in these two tissues may not be identical. In-vivo tests using a lethal dose of compound 48/80 (a potent histamine-releasing agent) demonstrated that triprolidine itself was the most active compound to protect the animal among all the isomeric compounds tested: in all isomeric pairs the E-configuration possessed superior activity over Z. The disposition of the aryl groups in these geometrically constrained compounds mimics that seen in the structurally related chiral pheniramines which are sp3 hybridized and whose absolute stereochemistry is known.

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.

Stereochemical studies of chiral H-1 antagonists of histamine: the resolution, chiral analysis, and biological evaluation of four antipodal pairs.

The resolution of the H-1 antihistamines chloropheniramine, dimethindene, carbinoxamine, and mebrophenhydramine is described. The optical purity of antipodal products is investigated by chiral HPLC (use of alpha 1-acid glycoprotein and beta-cyclodextrin columns) and NMR (spectra of beta-cyclodextrin inclusion complexes). Configurational relationships among the group are reviewed and assignments are confirmed and extended by circular dichroism evidence. Affinity constants of antipodal pairs for guinea pig ileum and cerebellum sites, determined by gut bath and binding experiments respectively, are reported together with some in vivo tests in man for central effects. Results are discussed in terms of configurational requirements for activity and variations in antipodal potency ratios within the group.

Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene.

1. The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+)-chlorpheniramine. 3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4. In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

HPLC and 1H-NMR study of chiral recognition in some thromboxane antagonists induced by beta-cyclodextrin.

The interaction of beta-cyclodextrin with a series of structurally related chiral thromboxane antagonists was investigated using NMR and RP-HPLC. HPLC studies used both a cyclodextrin bonded phase (Cyclobond I), and beta-cyclodextrin as a mobile phase additive with an achiral C8 column. Many of the compounds exhibited chiral recognition with beta-cyclodextrin in each technique, but only partial correlations between the three data sets were observed. HPLC and ROESY NMR data suggested the possibility of bimodal inclusion.

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.

Mass spectrometry of beta-lactam antibiotics with special reference to ionization by fast atom bombardment (FAB).

The mass spectral characteristics of the majority of penicillin and cephalosporin beta-lactam antibiotics in world-wide clinical use are presented and reviewed. Special attention is given to the spectra recorded under fast atom bombardment (FAB) conditions and novel data on many penicillins and cephalosporins are included. Mass spectrometry features of common degradation products of benzylpenicillin and of some synthetic intermediates are also presented. The data illustrate the value of FAB mass spectrometry in identifying members of this closely related group of antibiotics without need for derivatization.

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.

Structure-activity studies of fentanyl.

The preparation of analogues of fentanyl with para substituents in the anilino aromatic ring, anilino nitrogen separated from phenyl by methylene or bimethylene, and phenacyl replacing propionyl as the N-acyl substituent is reported. Although all para substituents examined depressed antinociceptive potency in rats, most analogues of this kind were more effective than morphine and the p-F, I, and Me derivatives were only a few-fold less active than fentanyl. Separation of anilino nitrogen from phenyl lowered potency with N-phenethyl analogues retaining reasonable levels of activity (greater than morphine). All the phenacyl analogues were of low potency or inactive. Diagnostic details of the mass spectra of analogues likely to be encountered as "designer drugs' are appended.

The structure of phenindamine base and salts in the solute state.

High-field NMR (13C and 1H) studies of phenindamine are reported which establish structures of the free base and some of its salts in the solute condition. The base exists as a mixture of two isomers which differ in double bond position (9-9a or 4a-9a) while most salts are 9-9a isomers. The clinically employed tartrate (Thephorin) is exceptional in being a 4a-9a ene. Salts of both double bond type exist in solution as mixtures of protonated epimers of variable epimeric ratio, that of the tartrate in D2O being approximately 1:1.

Electron-impact mass spectrometry of diuretic agents.

The mass spectrometric behaviour of nineteen diuretic agents in clinical use under conditions of 70 eV electron impact is analysed from reported and novel mass spectra. The molecular compositions of fragment ions are supported by high resolution data in selected cases, and a scheme presented for the rapid identification by MS of diuretics within the group.

Application of 1H nuclear magnetic resonance spectroscopy to the analysis of beta-lactam antibiotics and their common degradation products.

The (1)H NMR characteristics of the majority of penicillin and cephalosporin beta-lactam antibiotics in world-wide clinical use are presented. Some of the data are novel and include several high resolution (220, 400 MHz) spectra. The influence of solvent and ionisation state upon spectral parameters is discussed and a scheme of analysis proposed for identifying an unknown beta-lactam sample. Spectral features of common degradation products of benzylpenicillin and other penicillins are provided and the use of (1)H NMR spectroscopy in monitoring the breakdown of penicillin antibiotics described. Other aspects discussed are NMR studies of the stereochemistry, association and protein binding of beta-lactam antibiotics.

Fast-atom bombardment mass spectra of some pentapeptides related to natural enkephalins.

The mass spectral features of four diastereoisomeric pairs of peptides related to the enkephalins recorded under fast-atom bombardment conditions are presented and shown to provide evidence of molecular weight and amino acid content and sequence.