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Biomedical subjects

K C Rice

Publications and source records attributed to K C Rice.

At least 361 records · Page 20Linked to original sources
PubMed1981

Differential electrophysiological and behavioral responses to optically active derivatives of phencyclidine.

Dextro- and levorotatory isomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP) were synthesized. Both isomers inhibited spontaneous cerebellar Purkinje neuron firing when applied locally by pressure ejection. This effect was dose-dependent, with the (+)-isomer about 5--7 times more potent than the (-)-isomer. Both isomers also depressed rotarod performance in mice. Again, the (+)-isomer was about 5 times more potent than the (-)-isomer. Both rotarod performance and Purkinje cells discharge were depressed maximally 10--15 min after i.p. injection of drug. Our results suggest a correlation between behavioral performance and central neuron electrophysiological activity and suggest that the central actions of PCP or its derivatives are probably mediated at one locus, by a stereospecific mechanism.

Animals↗
PubMed1981

In vivo effects of two novel alkylating benzodiazepines, irazepine and kenazepine.

Intracerebroventricular administration of the alkylating benzodiazepines irazepine or kenazepine (20 nmol) resulted in a complete protection against convulsant doses of pentylenetetrazole (PTZ) for at least one hour, and a statistically significant protection for at least two and four hours, respectively. In contrast, administration of the non-alkylating parent benzodiazepine Ro-7/1986 or diazepam (20-60 nmol) resulted in no detectable anticonvulsants effects at fifteen minutes post-injection, the earliest interval examined. These results suggest that alkylating benzodiazepines which bind to brain benzodiazepine receptors in a non-competitive (covalent) fashion in vitro may exert a long lasting anticonvulsants effect by a similar mechanism.

Animals↗
PubMed1980

Heterogeneity of benzodiazepine receptors in the central nervous system demonstrated with kenazepine, an alkylating benzodiazepine.

Binding studies using the alkylating benzodiazepine kenazepine strongly suggest the existence of several populations of benzodiazepine receptors in the CNS. Kenazepine reacts noncompetitively and irreversibly with some receptors and competitively (reversibly) with others. Cerebellum contains the largest proportion (approx. 80%) of the noncompetitive type, while hippocampus and cortex contain a preponderance of competitive-type receptors (approx. 80 and 50%, respectively). The Hill coefficients for kenazepine are approx. 0.7 in cortex and cerebellum, and near unity in dorsal hippocampus. Different populations of benzodiazepine receptors may mediate different physiologic and pharmacologic effects in vivo.

Animals↗
PubMed1979

Deoxymorphines: role of the phenolic hydroxyl in antinociception and opiate receptor interactions.

Several 3-deoxy opioids and 3,6-dideoxydihydromorphine was synthesized to ascertain the effect of the phenolic hydroxyl group on antinociceptive potency and receptor binding affinity. Catalytic reduction of the 3-tetrazolyl ether derivatives of dihydromorphine provided the entry into the 3-deoxydihydro series. The prototype, 3-deoxymorphine, was prepared by lithium aluminum hydride reduction of 3-deoxy-N-carbethoxymorphinone, obtained via its 7-(phenylseleno) derivative. 3-Deoxydihydromorphinone and 3,6-dideoxydihydromorphine were found to be about as potent as, or more potent than, morphine in standard antiociceptive assays. Each of them, however, was less potent than the comparable 3-hydroxy analogue, and their binding affinity to the opiate receptor was substantially decreased. The epoxy ring in 3.6-dideoxydihydromorphine was found to increase the antinociceptive potency of the compound.

Analgesics↗
PubMed1979

Paradoxical effects of N-cyanoalkyl substituents upon the activities of several classes of opioids.

The pharmacological effect of the N-(beta-cyanoethyl) moiety is dependent on the opioid on which it is substituted. It caused a large increase in antinociceptive potency, in (--)-3-hydroxymorphinan and (--)-normetazocine, as compared with the N-methyl opioid. These cyanoethyl compounds do not substitute for morphine in morphine-dependent monkeys. This moiety also appears to greatly increase the ability of the opiate receptor to differentiate enantiomers. An ca. 100,000-fold difference in binding was noted between the epimeric N-(beta-cyanoethyl)-3-hydroxymorphinans and the normetazocines. The levo enantiomers have little acute toxicity and showed excellent therapeutic ratios. In contrast, the N-(beta-cyanoethyl) moiety on normorphine, norcodeine, and noroxymorphone did not appear to improve their pharmacological properties. Homologous N-cyanoalkyl opioids were less potent antinociceptives.

Alkylation↗
PubMed1978

Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone.

(+)-Naloxone was prepared in 26% overall yield in eight steps from (+)-7-bromodihydrocodeinone dimethyl ketal by a synthesis which excluded enantiomeric contamination. (+)-Naloxone was examined in three assay systems and found to have no more than 1/1000(-1)/10 000th the activity of (-)-naloxone; it can, thus, serve to test the stereospecificity of the biochemical and pharmacological actions of (-)-naloxone.

Adenylyl Cyclases↗
PubMed1978

Synthesis and antinociceptive activity of 7-methoxycodeine.

(-)-7-Methoxycodeine was synthesized from (-)-1-bromosinomeninone in three steps with an overall yield of 29%. The introduction of the 7-methoxy group into the C ring of codeine did not decrease its oral activity. 7-Methoxycodeine was unstable in acidic media. Its oral activity was however, not likely to be due to conversion to the acid-stable (-)-sinomeninone, since the latter was orally inactive.

Administration, Oral↗
PubMed1977

Stereospecific and nonstereospecific effects of (+)- and (-)-morphine: evidence for a new class of receptors?

The unnatural (+) enantiomer of morphine had minimal activity in three opiate assays in vitro: the rat brain homogenate binding assay, the electrically stimulated guinea pig ileum assay, and the inhibition of adenylate cyclase in neuroblastoma X glioma hybrid cell homogenates. When (+)-morphine was microinfected into the periaqueductal gray (a site known to mediate morphine analgesia) of drug-naive rats, there was only minimal analgesia, but the hyperresponsivity usually observed after microinfection of (-)-morphine occurred. Also, when (+)-morphine was microinfected into the midbrain reticular formation of drug-naive rats, rotation similar to that following microinjection of (-)-morphine occurred. These behaviors were not blocked by naloxone. Significantly, they typically occur in precipitated abstinence in morphine-dependent rats. These observations suggest that there are at least two classes of receptors, one stereospecific and blocked by naloxone and the other only weakly stereospecific and not blocked by naloxone, and that precipitated abstinence may be due, in part, to a selective blockade of receptors of the former class but not of the latter.

Adenylyl Cyclase Inhibitors↗
PubMed1977

Potential long acting opiate antagonists: preparation, pharmacological activity, and opiate-receptor binding of N-substituted 2'-hydroxy-5-methyl-9 alpha-propyl-6,7-benzomorphans.

A homologous series of N-substituted 2'-hydroxy-5-methyl-9 alpha-propyl-6,7-benzomorphans (hydrogen to octyl inclusive, allyl, and cyclopropylmethyl) was prepared. In contradistinction to the normetazocine, normorphine, and (-)-3-hydroxymorphinan series, the N-pentyl and N-hexyl derivatives do not have the analgesic potency of the parent N-methyl compound; instead, they are narcotic antagonists with a long duration of action. All of the N-substituted 9 alpha-propylbenzomorphans, except for methyl, heptyl, and octyl, have antagonist activity. The receptor binding constants of the N-alkyl compounds are uniformly two- to threefold lower than those of the N-substituted normetazocines.

Analgesics↗