Biomedical subjects

K C Rice

Publications and source records attributed to K C Rice.

At least 199 records · Page 11Linked to original sources

PubMed1990

Synthesis and structure-activity relationship of C5-substituted analogues of (+-)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine [(+-)-desmethyl-MK801]: ligands for the NMDA receptor-coupled phencyclidine binding site.

A series of eight C5-substituted analogues of (+-)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (1) have been prepared by the directed lithiation-alkylation (and acylation) of its (+-)-N-tert-butylformamidinyl derivative 2 followed by formamidine solvolysis. An additional 10 analogues were prepared by elaboration of the C5-ethyl ester derivative. Analogues possessing large (e.g. propyl and larger) lipophilic substituents displace [3H]-1-(1-thienylcyclohexyl)piperidine [( 3H]TCP) from the high-affinity phencyclidine (PCP) binding site in rat brain homogenates only at high concentrations (Ki greater than 1000 nM); however, the presence of a polar amino functionality (e.g. 2-aminoethyl) offsets this effect (Ki = 20 nM). Thus, the boundary condition for lipophilic substituents larger than ethyl appears to be polar in nature. Interaction of the 11 relatively small (MR less than 14) C5-substituted analogues of 1 with the high-affinity PCP binding site associated with the N-methyl-D-aspartate (NMDA) receptor is best described by the equation log (1/Ki) = -5.83F + 0.64 pi + 7.41 (r = 0.90).

Animals↗

PubMed1990

Probes for narcotic receptor mediated phenomena. 17. Synthesis and evaluation of a series of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet amide (U50,488) related isothiocyanate derivatives as opioid receptor affinity ligands.

A series of U50,488 related isothiocyanates was synthesized from enantiomerically pure (S,S)-(+)-trans-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-7] and (R,R)-(-)-trans-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-7]. DCC coupling of (+)- and (-)-7 with nitrophenylacetic acids followed by catalytic hydrogenation and treatment with thiophosgene afforded a series of six isomeric aryl isothiocyanate analogues of U50,488. Similarly, DCC coupling of (+)- and (-)-7 with (+)- and (-)-N-t-Boc-protected phenylglycines afforded four isomeric alkyl isothiocyanates. Evaluation of the isothiocyanates for their capacity to produce wash-resistant inhibition of mu, delta, and kappa sites in vitro was performed using rat and guinea pig brain membranes. None of the compounds was able to irreversibly inhibit binding of [3H]bremazocine to guinea pig and rat brain membranes (depleted of functional mu and delta receptors by pretreatment with acylating agents BIT and FIT). However, (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1] was able to specifically and irreversibly inhibit kappa receptors labeled by [3H]-U69,593: Incubation of rat brain membranes for 60 min at 25 degrees C with 1 microM of (-)-1 resulted in a wash-resistant reduction of the binding to 11.2 +/- 2.5% of the control. Binding analysis revealed the wash-resistant reduction in [3H]-U69,593 binding by (-)-1 to be through an increase in the Kd without effect on the Bmax. (-)-1 failed to effect mu or delta binding in rat or guinea pig brain under the same conditions. The enantiomer of (-)-1, (1R,2R)-trans-2-isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(+)-1], failed to affect kappa receptors labeled by [3H]-U69,593 under the same conditions as for (-)-1. (1S,2S)-trans-3-Isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-2] inhibited to 49.6 +/- 5.1% of the control, in a wash-resistant manner, kappa receptors labeled by [3H]-U69,593. However, (-)-2 was not as selective as (-)-1 since it also reduced [3H]DADLE (delta) binding to 82.4 +/- 8.0% of the control value. (1S,2S)-trans-4-Isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide [(-)-3] exhibited selective wash-resistant inhibition of delta receptors labeled by [3H]DADLE resulting in a reduction in binding to 42.9 +/- 4.2% of control.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1990

Synthesis and anticonvulsant activity of 1-phenylcyclohexylamine analogues.

Thirty-eight analogues of 1-phenylcyclohexylamine (PCA), a phencyclidine (PCP) derivative, were examined for their activities in the mouse maximal electroshock (MES) seizure test and in a motor-toxicity assay. In addition, we determined the binding affinities of the compounds for PCP acceptor sites in rat brain membranes labeled with [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine. Many of the analogues were protective against MES seizures (ED50s of 5-41 mg/kg, ip) and all of these compounds caused motor toxicity. The potencies in the motor toxicity and MES seizure tests showed a moderate correlation with the affinities for PCP sites. Several analogues exhibited a greater separation of potencies in the motor toxicity and MES seizure tests than did the parent compound PCA. These were obtained by (i) 3-methylation of the cyclohexyl ring trans to the phenyl ring, (ii) methoxylation at the ortho position on the phenyl ring, and (iii) contraction of the cyclohexane ring to form the corresponding cyclopentane.

Animals↗

PubMed1990

Synthesis, phencyclidine-like pharmacology, and antiischemic potential of meta-substituted 1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines.

A series of 1-[1-arylcyclohexyl]-1,2,3,6-tetrahydropyridines were prepared by the reaction between 1-(1-cyanocyclohexyl)-1,2,3,6-tetrahydropyridine (1) and an appropriately substituted Grignard reagent. The resulting compounds were tested for their phencyclidine binding site affinities. Selected compounds were then tested for their ability to produce ketamine appropriate responding in monkeys and/or to show neuroprotective effects in a baby rat hypoxia/ischemia model. While it was found that binding site affinity correlated well with discriminative stimulus effects, it was found to be a poor indicator of neuroprotective efficacy within this series.

Animals↗

PubMed1990

Synthesis and evaluation of N-substituted cis-N-methyl-2-(1-pyrrolidinyl)cyclohexylamines as high affinity sigma receptor ligands. Identification of a new class of highly potent and selective sigma receptor probes.

Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide] were recently reported to be potent sigma receptor ligands. In order to determine whether efficacy for the sigma receptor could be improved, a series of compounds related to the benzeneacetamides, N-substituted cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines, were synthesized and their structure-activity requirements were determined. The compounds were synthesized by starting with the previously reported (+/-)-, 1S,2R-(+)-, and 1R,2S-(-)-cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines. Analysis of sigma ([3H](+)-3-PPP), kappa ([3H]bremazocine and [3H]U69,593), dopamine-d2 ([3H](-)-sulpiride), and phencyclidine (PCP) ([3H]TCP) receptor binding in guinea pig brain revealed a number of highly potent and selective sigma receptor ligands. Notably, 1S,2R-cis-(-)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(2-naphthyl) acetamide [(-)-29] (Ki = 8.66 +/- 0.35 nM), (+/-)-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide [(+/-)-17] (Ki = 11 +/- 3 nM), 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine [(-)-44] (Ki = 1.3 +/- 0.3 nM), and 1R,2S-(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine. [(+)-44] (Ki = 6 +/- 3 nM) exhibited very high affinity at sigma receptors, by displacement of [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [( 3H]-(+)-3-PPP). These compounds showed insignificant affinity for kappa, dopamine, or PCP receptors, making them valuable tools for the study of sigma receptors. Furthermore, these compounds also exhibited enantioselectivity ranging from 5-fold for (+)- and (-)-44 to 160-fold for (+)- and (-)-29. Several other compounds showed equivalent selectivity but displayed lower sigma receptor affinity.

Animals↗

PubMed1990

Cannabinoid receptor localization in brain.

[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

Animals↗

PubMed1990

Characterization of benzodiazepine receptors with fluorescent ligands.

Fluorescein conjugates of the high-affinity benzodiazepine receptor ligands Ro 15-1788 and Ro 7-1986 were synthesized. The binding of these fluorescent ligands (BD 621 and BD 607) to benzodiazepine receptors was characterized by direct fluorescence measurement. Both the equilibrium dissociation constants (KD) of BD 621 and BD 607 and the maximum number of binding sites (Bmax) estimated by fluorescence monitoring were consistent with values obtained by using radioligand binding techniques. The binding of BD 621 and BD 607 assessed by fluorescence measurement was reversible, abolished by photoaffinity labeling with Ro 15-4513, and unaffected by a variety of substances that do not bind to benzodiazepine receptors. The potencies of chemically diverse benzodiazepine receptor compounds to inhibit fluorescent ligand binding were highly correlated (r = 0.94, P less than 0.001), with potencies obtained from radioligand binding techniques. These findings demonstrate the feasibility of using direct fluorescence measurement techniques to quantitate ligand-receptor interactions.

Animals↗

PubMed1990

BBB transport and rapid tissue binding of cyclofoxy: comparison of active and inactive enantiomers.

The "rapid-phase" brain distribution of 3H-labeled enantiomers of the opiate receptor antagonist cyclofoxy (CF), receptor active (-) and inert (+) forms, was measured during 20- to 180-s intravenous infusion in rats. [14C]iodoantipyrine was coinfused during these experiments to obtain a simultaneous measure of blood flow. The influx clearance (K1) across the blood-brain barrier (BBB) and the rapid binding equilibrium constant (Keq) were estimated in different brain regions for both enantiomers (2-compartmental model); a possible receptor binding process (k3) was also examined for (-)-CF (3-compartment model). K1 (0.46-0.91 ml.min-1.g-1), the capillary permeability-surface area product (PS; 0.75 approximately 1.4 ml.min-1.g-1) and the tissue extraction fraction (E; 0.6-0.7) were found to be identical for both enantiomers in the nonreceptor binding model; Keq was identical in cerebellum but larger for (-)-CF in other brain structures. The difference in Keq between the enantiomers (2-compartment model) correlated with the rank order of opiate receptor density observed in vitro and in vivo. These results suggest that concomitant use of (-)-CF and (+)-CF will be useful for in vivo receptor binding analyses.

Animals↗

PubMed1990

Anti-opioid receptor antibody recognition of a binding site on brain and leukocyte opioid receptors.

Opioid receptors reportedly exist on neuronal tissue of central and peripheral origin as well as on cells of the immune system. Previously, an opioid receptor has been purified from the neuroblastoma x glioma hybrid cell line, NG108-15 cells. In an effort to compare these results with opioid receptors isolated from primary neuronal tissue, we employed a methodology based on the molecular recognition theory to develop a monoclonal antibody which was used to isolate and biochemically characterize murine brain opioid receptors. We herein report the purification of an opioid receptor from mouse brain with a molecular weight of 65,000 daltons (range was 62-70 kD under reducing conditions) using a monoclonal antibody to an (the) opioid receptor. In situ labeling experiments with the delta-class selective opioid receptor affinity ligand, cis-(+)-3-methylfentanylisothiocyanate (SUPERFIT) of brain membrane confirmed these observations. Moreover, SUPERFIT, when coupled to the binding site, could block the recognition of the receptor by the monoclonal antibody. However, the selective, mu-class opioid receptor affinity reagent, 2-(p-ethoxybenzyl)-1-N,N-diethylaminoethyl-5-isothiocyanatobenz imidazole was ineffective at masking the binding site from recognition by the monoclonal antibody. Likewise, opioid-like receptors were purified from murine leukocytes which migrated at a molecular weight of 58,000 daltons under nonreducing conditions and 70,000 daltons under reducing conditions. In addition, immunoaffinity-purified receptor is shown to specifically bind the delta-class-selective opioid ligand, cis-(+)-3-methylfentanylisothiocyanate as well as the endogenous opioid peptides, beta-endorphin and [Met]-enkephalin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990