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Biomedical subjects

K R Scott

Publications and source records attributed to K R Scott.

At least 37 records · Page 2Linked to original sources
PubMed1994

Synthesis, reactions, and preliminary evaluations of enaminone esters.

The objective of this work was to design enaminone esters that would possess potential medicinal properties. The reaction between beta-hydroxyketo esters and primary or secondary amines yielded secondary or tertiary enaminone esters, respectively. The UV spectra of the enaminone esters were determined in acidic, alkaline, and neutral media; the spectra have a hypsochromic shift in acidic media in comparison with neutral media. The enaminone esters provided nucleophilic and electrophilic sites for a variety of reactions. Thus, the enaminone esters were converted into enaminone amides and O-alkylation products exclusively. Although the enaminone esters were generally resistant to reduction by metal hydrides, one unhindered enaminone ester was reduced to an alcohol with sodium borohydride. Another enaminone ester reacted with guanidine to give the corresponding quinazolinone. Due to the variety of nucleophilic and electrophilic sites in the enaminone system, enaminone esters possess a great potential as reaction intermediates and medicinal compounds. Preliminary evaluations of the enaminone esters revealed a histaminergic effect, uterine relaxant properties, and anticonvulsant activity.

Animals↗
PubMed1994

Nuclear magnetic resonance studies of anticonvulsant enaminones.

1H nuclear magnetic resonance (NMR) spectra of enaminones were determined and compared to the anticonvulsant activity of the compounds. Although the precise employment of the NMR data to predict anticonvulsant activity of the enaminones could not be established, general inferences were made. The NMR data confirmed that the enaminones existed predominantly in the amino tautomer, and no evidence was found for the imino tautomer. The ketamine form of the enaminones was supported by the observed spin-spin splittings of the NH with the alpha-protons on certain enaminones. The NH of secondary enaminones was very important in conferring anticonvulsant activity to the enaminones. The peak for the NH proton which could be seen between delta (ppm) 4.50 and 9.70 was present in all of the active enaminones. The tertiary enaminones, which were devoid of the NH proton, were uniformly inactive. It appeared that a combination of steric and electronic effects, lipophilicity, and hydrogen bonding were necessary for the anticonvulsant activity of the enaminones. The cyclic enaminones existed in the trans-S-trans fixed conformation, and the NMR data supported our hypothesis that enantioselectivity is retained in synthesizing enaminones from cyclic, diasteriomeric 1,3-diketones. In addition, the AB system and many unique features were observed in some enaminones. The para, meta, and ortho substituted patterns were observed for monosubstituted phenyl protons, and the NMR patterns for di- and trisubstituted phenyl groups were elucidated.

Anticonvulsants↗
PubMed1994

Synthesis and evaluation of amino analogues of valproic acid.

Valproic acid, an antiepileptic drug, is extensively metabolized in humans. Two putative metabolites, 2-n-propyl-3-aminopentanoic acid (3-aminovalproic acid, 3-amino-VPA; 2a) and 2-n-propyl-4-aminopentanoic acid (4-amino-valproic acid, 4-amino-VPA; 4a), which may result from the transamination of the respective keto acids 1a and 3a may explain the unusual extended seizure protection elicited by valproic acid. The title compounds were synthesized as their diasteriomeric ethyl esters 2b and 4b and submitted for anticonvulsant evaluation by the Antiepileptic Drug Development Program of the National Institute of Neurological and Communicative Disorders and Stroke. The results verified our hypothesis, as 4b was active in the subcutaneous pentylenetetrazol (scMet) evaluation at 30 mg/kg. Both compounds were highly toxic at 300 mg/kg.

Animals↗
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↗
PubMed1992

Vertically oriented upper eyelid nerve fibers. A clinical, anatomical and immunohistochemical study.

Vertically oriented suborbicular nerve fibers are frequently encountered during upper eyelid surgery. It has not been well established whether these fibers are terminal motor branches of the facial nerve (VII) or sensory branches of the ophthalmic nerve (V-1). To investigate the origin of these nerve fibers, three different techniques were used: (1) intraoperative nerve stimulation; (2) cadaver dissection; and (3) immunohistochemical analysis. The results of all three investigative methods are in agreement and conclusively demonstrate that these fibers represent sensory branches of the ophthalmic nerve (V-1) and not motor branches of the facial nerve (VII). Anatomical dissection showed that the sensory fibers to the upper eyelid do not travel solely within the suborbicular fascial plane, but also course in the preorbicular plane and within the orbicularis muscle itself. The terminal branches of the facial nerve to the upper eyelid innervate the orbicularis oculi from the undersurface and in a horizontal orientation. Clinical correlation of these findings is discussed.

Choline O-Acetyltransferase↗
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↗
PubMed1991

Temporal artery biopsy technique: a clinico-anatomical approach.

A positive temporal artery biopsy is required to conclusively establish the diagnosis of temporal arteritis. The temporal artery biopsy technique we describe is based on the anatomical branching patterns of the superficial temporal artery, the various fascial layers, and the location of the temporal branches of the facial nerve. Special emphasis is placed on avoiding facial nerve trauma during a biopsy of the frontal branch of the superficial temporal artery. Proper surgical technique combined with a working knowledge of the anatomy of the temporalis region enhances the safety of a temporal artery biopsy procedure.

Biopsy↗
PubMed1989

Peripunctal melanocytic nevi. Distinctive clinical findings and differential diagnosis.

A peripunctal nevus is a rare lesion of the eyelid margin, six examples of which are included in this report. The lesions all involved the lower punctum and had been present for many years without producing epiphora. In addition to their variable clinical pigmentation and translucent appearance on biomicroscopy, all shared several other diagnostically useful clinical features: an overall dome-shape with a fine micronodularity; a prominent ramifying vascularity; and, most importantly, circumferentially swollen punctal lips that created a slit-like punctal orifice. Histopathologically, the lesions were predominantly or exclusively subepithelial melanocytic nevi and were demonstrated not to compress the punctum or canaliculus. Infiltration of the nevus cells within the orbicularis striated muscle fibers was a common finding owing to the latter's superficial location in the eyelids. If patients request excision for cosmetic reasons, these lesions are best managed by a horizontal circular shave excision with the temporary placement of a silicon punctual plug. The differential diagnosis includes cyst, papilloma, melanoma, and basal cell carcinoma.

Adolescent↗
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↗
PubMed1984

Potential inhibitors of tyrosine hydroxylase and dopamine-beta-hydroxylase.

A series of methyl-substituted 1,2,3,4-tetrahydrocarbazoles was synthesized and screened for in vitro activity against tyrosine hydroxylase and dopamine-beta-hydroxylase. The most potent compounds were evaluated for inhibition of norepinephrine biosynthesis in rats. The results indicated no significant decrease in norepinephrine levels at three dosage levels.

Animals↗