Biomedical subjects

K M Kirkland

Publications and source records attributed to K M Kirkland.

5 recordsLinked to original sources

PubMed2001

Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.

Animals↗

PubMed1994

Rapid, high-resolution high-performance liquid chromatographic analysis of antibiotics.

A HPLC column devised for high separation speed combined with highly practical operating features has been found useful for separating antibiotics. Important characteristics involved compromises in packing particle size, column configuration and support-stationary phase combinations. We determined that these columns are useful for rapid, high-resolution separations with unmodified state-of-the-art HPLC equipment without the extra-column band-broadening effects typical of so-called "fast" HPLC columns. The proposed columns feature efficient sterically-protected monofunctional silane stationary phases that provide good separation reproducibility and high column stability. The combination of these unique bonded silanes and a highly purified, less-acidic silica support give superior peak shapes for antibiotic compounds. The proposed column configuration can halve separation times and double peak heights without loss in resolution, compared to widely used analytical columns. Increased mobile phase flow-rates permit even faster separations of antibiotics with only modest loss in resolution and peak heights for trace analyses in biological systems.

Animals↗

PubMed1993

Substituted 3-(phenylmethyl)-1H-indole-5-carboxamides and 1-(phenylmethyl)indole-6-carboxamides as potent, selective, orally active antagonists of the peptidoleukotrienes.

Substituted indole-5-carboxamides and indole-6-carboxamides have been found to be potent and selective antagonists of the peptidoleukotrienes. Initial derivatives of these series (4-[[5-[(cyclopentylmethyl)carbamoyl]-1-methylindol-3-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (5a) and 4-[[6-[(cyclopentylmethyl)carbamoyl]-3-methylindol-1-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (6a), respectively), when compared to the corresponding indole amides (e.g. 28 and 29), were found to be approximately 10-fold less potent in vitro and substantially less active when administered orally to guinea pigs. Efforts to improve the potency of the title series by variation of the amide, indole, or sulfonamide substituents led to compounds of comparable in vitro potency to ICI 204,219, but of somewhat lower oral activity. A trend which suggested that more lipophilic transposed amides were needed to increase oral activity was exploited with some success and has led to the discovery of 5q (4-[[5-[(2-ethylbutyl)-carbamoyl]-1-ethylindol-3-yl]methyl]- 3- methoxy-N-[(2-methylphenyl)sulfonyl]benzamide), a transposed amide with subnanomolar affinity for the leukotriene receptor and an oral ED50 of 5 mg/kg in a model of asthma in guinea pigs. In this model, ICI 204,219 was active at 0.4 mg/kg. The absolute bioavailability of 5q has been found to be 28% in the rat, as compared to 68% for ICI 204,219, with significant levels of 5q observed in the blood of rats up to 24 h postdose.

Administration, Oral↗

PubMedDate not supplied

Tracazolate metabolites in rat tissue.

Tracazolate (4-n-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b] pyridine-5-carboxylic acid ethyl ester) undergoes extensive biotransformation to lipophilic metabolites following oral dosage to male rats. Twenty-one metabolites were identified in a plasma hexane extract by mass spectrometry. Coadministration of unlabeled tracazolate with its stable carbon-13 isotope expedited the isolation and identification of 11 biotransformation products. The various metabolites resulted from either hydrolysis, oxidation, dealkylation, or conversion of an ethyl group to a vinyl group and also from combinations of these biotransformation reactions. Brain extract contained tracazolate and 12 of the metabolites found in plasma. Extracts of fat contained tracazolate and nine of the plasma metabolites. An uncommon type of metabolite less polar than tracazolate (1-vinyl tracazolate) was isolated by HPLC and identified by mass spectrometry.

Adipose Tissue↗

PubMedDate not supplied

Metabolism of tracazolate. Metabolites in dog and rat urine.

The urinary metabolites of tracazolate [4-n-butylamino-1-ethyl-6-methyl-1H-pyrazolo (3,4-b) pyridine-5-carboxylic acid ethyl ester], an anxiolytic agent, obtained from rats and dogs dosed with 14C-labeled tracazolate have been characterized. No unchanged tracazolate was detected. Fifteen metabolites were identified in dog urine, seven of which had not previously been found in rat blood and tissue. Eleven of these metabolites were also found in rat urine. The metabolites were formed by deesterification to the 5-carboxylic acid; N-deethylation of the pyrazole ring: oxidation at the gamma-position of the n-butylamino side chain; oxidation of the terminal carbon of this side chain; loss of the n-butylamino group; and hydroxylation of the 6-methyl group followed by condensation with the 5-carboxylic acid to form gamma-lactones. The major metabolites in dog urine were the desethyl-desbutyl-deesterified compound, the desbutyl-deesterified compound, and the desbutyl-desethyl-lactone. Loss of the butyl side chain and, also, lactone formation, appeared to occur to a lesser extent in the rat than in the dog.

Animals↗