Search PubMed⌕ Search

Biomedical subjects

J M Nicholson

Publications and source records attributed to J M Nicholson.

35 records · Page 2Linked to original sources
PubMed1993

Synthesis and anticonvulsant activity of enaminones. 2. Further structure-activity correlations.

This report continues the in-depth evaluation of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate , 1 (ADD 196022), and methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 2, two potent anticonvulsant enaminones. These compounds were evaluated employing the amygdala kindling model. Neither 1 nor 2 was active against amygdala kindled seizures, further supporting the corneal kindled model as a definitive tool for antielectroshock seizure evaluation as previously reported. Additional intraperitoneal (ip) data on 1 revealed toxicity at 24 h at 100 mg/kg. Several active analogs have been prepared with the view to minimizing toxicity. In a special ip rat screen developed by the Antiepileptic Drug Development (ADD) Program, these newer analogs were evaluated for protection against maximal electroshock seizures (MES) at 10 mg/kg and neurotoxicity at 100 mg/kg. From this screen, several compounds were shown to be safer alternatives, the most notable was methyl 4-[(p-bromophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate, 13. Compound 13 had an ip ED50 of 4 mg/kg in the rat and a TD50 of 269 mg/kg, providing a protective index (TD50/ED50) of > 67. By variation in the ring size, additional aromatic substitutions and the synthesis of acyclic analogs, these newer compounds provide a more definitive insight into the structure-activity correlation. CLOGP evaluation and molecular modeling studies are also provided to further elaborate the molecular characteristics of potential anticonvulsant enaminones.

Animals↗
PubMed1992

Synthesis and anticonvulsant activity of enaminones.

A new series of novel enaminones has been synthesized from cyclic beta-dicarbonyl precursors which were condensed with morpholine, pyrrolidine, phenethylamine, hydrazines, substituted benzyl amines, and substituted anilines. These compounds were subsequently evaluated for anticonvulsant activity in a variety of anticonvulsant models by the National Institute of Neurological and Communicative Disorders and Stroke and in our laboratory. Several of these compounds exhibited potent anticonvulsant activity with a remarkable lack of neurotoxicity. The most active analog, methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxo-cyclohex-3-en-1-oate++ + (27), was protective in the maximal electroshock (MES) seizure test in the rat with an oral ED50 of 5.8 mg/kg with no toxicity noted at doses up to 380 mg/kg, thus providing a protective index (TD50/ED50) of greater than 65.5. A similar protective index for 27 was noted upon intraperitoneal (ip) administration in mice. The anticonvulsant effect of 27 occurred within 15 min of administration and the compound remained active beyond 4 h. Compound 27 was also active in the rat corneal kindled model. The application of Free-Wilson analysis to structure-activity correlation in this series is discussed.

Amines↗
PubMed1991

Synthesis and anticonvulsant activity of imidooxy derivatives.

Previous results of anticonvulsant activity in several imidooxy carboxylates related to (aminooxy)acetic acid in young chicks, prompted an in-depth reinvestigation of these analogues in mice. A series of 22 succinimidooxy, phthalimidooxy, and naphthalimidooxy carboxylates were synthesized and evaluated for anticonvulsant activity by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS). Methyl (succinimidooxy)acetate (2d), ethyl (succinimidooxy)acetate (2e), methyl (phthalimidooxy)acetate (3d), ethyl (phthalimidooxy)acetate (3e), and ethyl 2-(phthalimidooxy)propionate (3g), which were initially found to be active as anticonvulsants in young chicks were uniformly inactive in the Phase I seizure tests involving maximal electroshock (MES), pentylenetetrazol (scMet), or neurologic toxicity toxicity (Tox). Several newer analogues, ethyl (succinimidooxy)formate (2c) and methyl 3-(phthalimidooxy)-2-methylacrylate (4h) were found to be active in the scMet (3a) or both (4h) evaluations. Most interesting was the anticonvulsant results of N-(benzyloxy)-2-azaspiro[4,4] nonane-1,3-dione (5b), which displayed anti-MES activity and a protective index (TD50/ED50) of greater than 4.5.

Animals↗
PubMed1985

Spirosuccinimides as potential anticonvulsants.

A series of spirosuccinimides was synthesized and evaluated for anticonvulsant activity. The study was designed to apply the Topliss approach to structure-activity correlations in this novel series of 2-substituted-2-azaspiro[4.4]nonane-1,3-diones and 2,4-disubstituted-2-azaspiro[4.4]nonane-1,3-diones. While no correlation was noted with the 2-substituted derivatives, a good correlation was obtained in the 2,4-disubstituted series, indicating that anticonvulsant activity was related to increasing tau values. The results of these anticonvulsant tests are presented and a rational approach to the structure-activity relationships of spirosuccinimides is provided.

Animals↗
PubMed1985

Spiro[4.5] and spiro[4.6] carboxylic acids: cyclic analogues of valproic acid. Synthesis and anticonvulsant evaluation.

Spiro[4.5]decane-2-carboxylic acid (12a), spiro[4.5]decane-2,2-dicarboxylic acid (11a), spiro[4.6]undecane-2-carboxylic acid (12b), spiro[4.6]undecane- 2,2-dicarboxylic acid (11b), and spiro[4.6]undecane-2-acetic acid (13) were synthesized by an improved method and evaluated for anticonvulsant activity. These analogues were synthesized to evaluate the role of the carboxylic acid group as an essential substituent in valproic acid (di-n-propylacetic acid, 1). Carbocyclic spiranes are known to resist metabolic alteration so that any activity elicited by these compounds would be due to the carboxylic acid function and not to any metabolic change. Spiro[4.6]undecane-2-carboxylic acid (12b) was the most active analogue tested and the pentylenetetrazol and picrotoxin evaluations of 12b compared favorably to 1. However, 12b failed to provide adequate protection against maximal electroshock seizures, bicuculline, or strychnine in mice. Possible reasons for these results are discussed.

Animals↗
PubMed1980

Mammalin tyrosinase. Stoichiometry and measurement of reaction products.

The substrates and intermediates involved in the conversion of tyrosine or 3,4-dihydroxyphenylalanine into melanin by autooxidation, or tyrosinases (monophenol, dihydroxyphenylalanine:oxygen oxidoreductases, EC 1.14.18.1) of mushroom or mammalian melanocyte origin, was studied by a variety of enzymic assays, and by amino acid analysis. It was found that the classic pathway of melanin formation was followed, and that the proposed alternate pathway involving formation of the intermediate 3,4,6-trihydroxyphenylalanine was not a functional route, since nascent trihydroxyphenylalanine was not detectable. The ability of isolated mammalian tyrosinases to convert tyrosine into dihydroxyphenylalanine was unequivocably demonstrated. The polymerization of monomers into melanin was followed by the use of specifically labelled precursors, and the data indicate that uncyclized and carboxylated derivatives are not incorporated into the polymer in vitro. It was found that although in most respects the melanin produced from tyrosine by mushroom and mammalian tyrosinses are similar, the control mechanisms involved in the expression of melanin formation in these organisms must differ greatly.

Amino Acids↗
PubMed1979

Chronic obstructive pulmonary disease (COPD) in horses: aetiological studies: responses to intradermal and inhalation antigenic challenge.

Micropolyspora faeni and Aspergillus fumigatus were identified as common causes of respiratory hypersensitivity in horses affected with chronic obstructive pulmonary disease (COPD). Rye grass pollen and an Actinomycete evoked respiratory allergy in a few horses. Not infrequently, individual horses were found to have respiratory hypersensitivity to two or more antigens. The methods used to examine for allergy were intradermal testing and inhalation challenge with environmental antigens. An intradermal test using an M faeni extract was demonstrated to be suitable for diagnostic use in horses previously accurately diagnosed as suffering from COPD. In contrast, the A fumigatus antigen used proved unsatisfactory for such a purpose. Skin reaction to M faeni and A fumigatus extracts by horses affected with COPD indicated that the hypersensitivity was a dual one--a weak response shortly after injection followed by an Arthus-like response 4 to 8 hours later. As a parameter for monitoring responses to inhalation challenge, maximum intrathoracic pressure change (max delta Ppl) proved satisfactory, whereas changes in partial pressure of arterial oxygen (PaO2) did not.

Animals↗
PubMed1979

Chronic obstructive pulmonary disease (COPD): factors influencing the occurrence.

Breed, age, weight, type of work performed, seasonal onset, poor ventilation and exposure to moulds in the habitat were investigated in relation to the occurrence of chronic obstructive pulmonary disease (COPD). COPD was most commonly detected in showjumping and hacking horses. The older a horse, the more likely it was to become affected although most were 6 to 10 years of age. Of the horses in this sample of the population, which was not a random one, thoroughbred horses were affected least and ponies most often. The high incidence in ponies was related to their more frequent exposure to poor quality fodder and bedding. Most horses are exposed to the hazard of moulds, but more affected horses were so exposed than those not affected with COPD. Poor ventilation of the stable increased the chance of a horse becoming affected. Sex, body weight and season of onset of coughing had no influence on the occurrence of the disease.

Age Factors↗
PubMed1979

The presence of precipitating antibodies in the sera of horses with chronic obstructive pulmonary disease (COPD).

The sera of horses affected and not affected with chronic obstructive pulmonary disease (COPD) were examined for precipitins to Micropolyspora faeni and Aspergillus fumigatus. Precipitins to both antigens were not restricted to COPD cases but occurred more frequently in animals affected with COPD. Many animals without detectable precipitins responded clinically to inhalation challenge with these antigens.

Animals↗
PubMed1979

Abnormal protein synthesis in malignant melanoma cells.

Abnormal proteins in neoplastic cells are present in a variety of animal tumor systems. Our laboratory has isolated several of these abnormal proteins from murine malignant melanoma by preparative gel electrophoresis; these proteins are similar in many respects to analogous proteins found in normal tissues. Examination of these proteins by polyacrylamide gel electrophoresis, amino acid analysis, carboxy and amino terminal analysis and peptide mapping after cyanogen bromide cleavage, supports the theory that these abnormal proteins are the result of deleted sequences in the peptide chain during the attempted synthesis of normal proteins in neoplastic tissue.

Amino Acids↗
PubMed1978

Mammalian tyrosinase. Structural and functional interraltionship of isozymes.

The isozymes of tyrosinase from normal and malignant melanocytes were studied; the data indicates that each consists of a basic tyrosinase polypeptide, and differs by post-translational modifications. T3 represents the de novo form of the enzyme; it is converted to T1 in vivo by the addition of sialic acids and neutral sugars, and in turn, to T4 by complexing with mealanosomal membrane constituents. The T2 isomer is suggested to be an artefact of the electrophoretic procedure, and due to deamidation of T3. It is shown that the apparent kinetics of enzyme activity are unafffected by any of these modifications.

Animals↗
PubMed1977

Intracellular localization of tumor-associated antigens in murine and human malignant melanoma.

Cross-reacting tumor-associated antigens have been demonstrated to be present in the cytoplasm of melanocytes in malignant melanoma. We have utilized both the leukocyte migration inhibition and the lymphocyte stimulation assays to determine the intracellular location(s) of these antigens in both human malignant melanoma and B-16 murine melanoma. The results of both assays indicate that this antigen(s) is associated with the membranous organelles, particularly the melanin granules, and is not found in the soluble components of the cytoplasm, as suggested by other studies.

Animals↗