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At least 145 records · Page 8Linked to original sources

PubMed1992

A comparison of the discriminative stimulus properties of delta 9-tetrahydrocannabinol and CP 55,940 in rats and rhesus monkeys.

CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol] is a potent bicyclic analog of delta 9-tetrahydrocannabinol (THC) which has been used as a probe for a cannabinoid recognition site in neural tissue. In the present study, CP 55,490 was evaluated for delta 9-THC-like effects in rats and rhesus monkeys trained to discriminate delta 9-THC from vehicle. Rats trained to discriminate delta 9-THC (3.0 mg/kg i.p.) from vehicle were tested with various doses of delta 9-THC and CP 55,940 at both 30 and 90 min postinjection. Catalepsy was measured immediately after these operant tests using an adaptation of the mouse ring-test. In rats, CP 55,940 substituted for delta 9-THC at both 30 and 90 min postinjection at a dose of 0.1 mg/kg that had minimal effects on rates of responding. Doses of delta 9-THC (greater than 3.0 mg/kg) and CP 55,940 (greater than 0.1 mg/kg) that reduced response rates by greater than 50% also produced substantial increases in catalepsy. CP 55,940 and delta 9-THC had a similar time course for discriminative stimulus effects, but CP 55,940 was about 30 times more potent. In monkeys, the training dose of delta 9-THC ranged from 0.04 to 0.16 mg/kg i.m., adjusted individually to minimize response-rate disruption. After training, monkeys were tested with various doses of delta 9-THC and CP 55,940 at 30 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1978

The effect of cyclohexane derivatives on selection of bacterial groups forming activated sludge microflora.

The effect of cyclohexanol, cyclohekxanon and cyclohexylamine on the selection of bacteria in a model population composed of bacteria isolated from activated sludge was examined. The initial population consisted of both gram-positive and gram-negative bacteria. The latter, which accounted for 90-97% of the population, belonged mainly to three Pseudomonas groups and the Enterobacteriaceae, Vibrio-Aeromonas, Achromobacter-Alcaligenes and Flavobacterium groups. Seven day growth in medium containing cyclohexane derivatives caused pronounced qualitative changes in the population. The compounds favored the development of bacteria of the genus Pseudomonas and inhibited the growth of all other gram-negative bacteria. The direction of selection was independent of the type of cyclohexane derivative.

Alcaligenes↗

PubMed1993

Inversion of the substrate specificity of yeast alcohol dehydrogenase.

The relationship between the size of the substrate binding pocket and the catalytic reactivities with varied alcohols was studied with the Saccharomyces cerevisiae alcohol dehydrogenase I (ScADH) and compared with the liver enzymes from horse (EqADH, EE isoenzyme) and monkey (MmADH alpha, alpha-isoenzyme). The yeast enzyme is most active with ethanol, and its activity decreases as the size of the alcohol is increased, whereas the activities of the liver enzymes increase with larger alcohols. The substrate pocket in ScADH was enlarged by single substitutions of Thr-48 to Ser (T48S), Trp-57 to Met (W57M), and Trp-93 to Ala (W93A), and a double change, T48S:W93A, and a triple, T48S:W57M:W93A. The T48S enzyme has the same pattern of activity (V/K) as wild-type ScADH for linear primary alcohols. The W57M enzymes have lowered reactivity with primary and secondary alcohols. The W93A and T48S:W93A enzymes resemble MmADH alpha in having an inverted specificity pattern for primary alcohols, being 3- and 10-fold more active on hexanol and 350- and 540-fold less active on ethanol, and are as reactive as the liver enzymes with long chain primary alcohols. The three Ala-93 enzymes also acquired weak activity on branched chain alcohols and cyclohexanol.

Aldehyde Dehydrogenase↗

PubMed1976

Evaluation of 2-benzylidenecyclohexanones and 2,6-bis(benzylidene)cyclohexanones for antitumor and cytotoxic activity and as inhibitors of mitochondrial function in yeast: metabolism studies of (E)-2-benzylidenecyclohexanone.

Some 2-benzylidenecyclohexanones, 2,6-bis(benzylidene)cyclohexanones, and related compounds were evaluated for antitumor and cytotoxic activities; (E)-2-benzylidenecyclohexanone (Ia) was shown to have significant cytotoxic properties and a potent inhibitory effect on yeast mitochondria. After intraperitoneal injection of Ia, unchanged drug and a metabolite, tentatively identified as 2-(p-hydroxybenzyl)cyclohexanol, were found in the urine. No metabolites were found in the feces. Oral administration of Ia afforded three unidentified metabolites in the urine and three unidentified metabolites in the feces.

Animals↗

PubMed1988

[3H]vesamicol binding in brain: autoradiographic distribution, pharmacology, and effects of cholinergic lesions.

An autoradiographic analysis of high-affinity binding sites for the vesicular acetylcholine transport blocker [3H]vesamicol (2-(4-phenylpiperidino) cyclohexanol; AH 5183) was conducted in rat brain. [3H]Vesamicol binding was displaced 52-99% by DPPN [( 2,3,4,8]-decahydro-3-(4-phenyl-1-piperidinyl)-2-napthalenol) (IC50 = 14 nM) and by ketanserin (500 nM), haloperidol (43 nM), and vesamicol analogs, but not by drugs selective for adenosine, adrenergic, amino acid, calcium channel, monoaminergic, opioid, PCP, sigma, or several other receptor classes. [3H]Vesamicol binding was most concentrated in the interpeduncular nucleus and fifth and seventh cranial nerve nuclei. Moderate binding was found in the lateral caudate-putamen, medial nucleus accumbens, olfactory tubercle, vertical and horizontal diagonal bands of Broca, and basolateral amygdala. The distribution of [3H]vesamicol binding was similar to distributions of acetylcholine (r = 0.88), acetylcholine esterase (r = 0.97), choline acetyltransferase (ChAT) (r = 0.97), and [3H]hemicholinium-3 binding sites (r = 0.95-0.99). Lower correlations were obtained between [3H]vesamicol and muscarinic receptor densities (r = 0.50-0.70). Few exceptions to the match between binding and cholinergic neuronal markers were found, e.g., the molecular layer of the cerebellum and the thalamus. Lesions of cholinergic neuronal projections to the neocortex or hippocampus reduced [3H]vesamicol binding in each of these regions, but to a lesser extent than reductions in ChAT. [3H]Vesamicol binding sites appear to be anatomically associated with brain cholinergic neurons, a locus that is consistent with the control by this site of vesicular acetylcholine uptake.

Acetylcholine↗

PubMed1994

Keratinocyte-derived proinflammatory key mediators and cell viability as in vitro parameters of irritancy: a possible alternative to the Draize skin irritation test.

This study is aimed at the development of a cell culture assay which may supplement or replace the animal Draize skin irritancy test. Using human keratinocytes, the measurement of proinflammatory eicosanoid and interleukin-1 alpha release and of the impairment of cell viability have provided a suitable in vitro/in vivo correlation for at least three surfactants. The in vitro study has been extended using structurally unrelated, pharmacologically relevant compounds including ethanol, glycerol, cyclohexanol, acetone, benzoic acid, phenol, acrylamide, triethanolamine, Tween 80, sodium dodecyl sulfate, benzalkonium chloride, NiSO4, SnCl2, and ZnCl2. Time- and dose-response studies were used to establish half-maximal stimulatory (SC50) and inhibitory (IC50) as well as 10-fold stimulatory (ED10) concentrations for arachidonic acid release, cytotoxicity, and IL-1 alpha release, respectively. Based upon these values a similar ranking has been obtained for the mildly acting acetone, ethanol, glycerol, and Tween 80 and for the severely acting A23187, benzalkonium chloride, and sodium dodecyl sulfate. With respect to all other test compounds, substantial variation occurred indicating that all three test parameters provide a more complete characterization of the test compound's potency than a single endpoint. These data are ready to be validated by a controlled clinical study aimed at a qualitative and quantitative evaluation of the symptoms of skin inflammation in volunteers.

Animal Testing Alternatives↗

PubMed1981

Measurement of the urinary metabolites of N-hexane, cyclohexane and their isomers by gas chromatography.

A gas chromatographic method for analyzing the urinary metabolites of n-hexane (2-hexanol, 2,5-hexanedione, 2,5-dimethylfuran and gamma-valerolactone), of 2-methylpentane (2-methyl-2-pentanol), of 3-methylpentane (3-methyl-2-pentanol), and of cyclohexane (cyclohexanol) was developed. Processing of urine and the gas chromatographic conditions are described. The recovery rate of all hexane metabolites, except 2,5-dimethylfuran, ranged between 92 and 100%. The variation coefficient of metabolites determination was between 1.5 and 5%, apart from 2.5-dimethylfuran determination for which the variation coefficient was 15%. The detection limits ranged between 0.2 and 0.7 mg/l and between 0.05 and 0.1 mg/l when a packed or capillary column was used. Results obtained from a packed and capillary column are discussed.

Biotransformation↗

PubMed1988

Evidence to suggest that the spontaneous release of acetylcholine from rat hippocampal tissue is carrier-mediated.

The effect of L- and D-stereoisomers of 2-(4-phenylpiperidino) cyclohexanol (AH 5183) on the spontaneous release of acetylcholine (ACh) from rat hippocampal tissue was studied. L-AH 5183 was approximately 100 times more potent than was D-AH 5183 in reducing spontaneous ACh release. Spontaneous ACh release was also temperature dependent. These results may suggest that the spontaneous release of ACh from brain tissue is carrier-mediated.

Acetylcholine↗

PubMed1993

Ethanol metabolism in isolated hepatocytes. Effects of methylene blue, cyanamide and penicillamine on the redox state of the bound coenzyme and on the substrate exchange at alcohol dehydrogenase.

Ethanol metabolism in hepatocytes increases the NADH/NAD+ ratio. The mechanism was investigated by measurements of the redox state of the coenzyme bound to alcohol dehydrogenase and of ethanol-acetaldehyde exchange and concomitant hydrogen transfer between ethanol molecules. Isolated hepatocytes from fed rats were incubated with cyclohexanone and cyclohexanol or with [1,1-2H2]-and [2,2,2-2H3]ethanol, followed by gas chromatographic determination of the redox state and isotope analysis of the ethanol by gas chromatography-mass spectrometry, respectively. Cyanamide and methylene blue decreased the redox shift caused by ethanol and increased the rates of acetaldehyde reduction during the exchange. Both drugs increased the extent of hydrogen transfer between ethanol molecules during oxidoreduction. Penicillamine had no significant effect on the ethanol-induced change in redox state of the bound coenzyme although it decreased the rate of acetaldehyde reduction. The results indicate that methylene blue inhibits aldehyde dehydrogenase and that accumulation of acetaldehyde decreases the redox effects of ethanol. The redox effect appears to result primarily from rapid elimination of acetaldehyde and equilibration with the NAD system on the alcohol dehydrogenase, but is not enhanced by further decreases in acetaldehyde concentration. Thus, penicillamine could probably be used to decrease the concentration of acetaldehyde without increasing the redox effects.

Acetaldehyde↗

PubMed1995

Vesamicol analogues as sigma ligands. Molecular determinants of selectivity at the vesamicol receptor.

The present study compares the affinities of 2-(4-phenylpiperidino)cyclohexanol (vesamicol, 1) and selected analogues of the latter at the vesamicol receptor (VR) with the corresponding affinities at sigma 1 and sigma 2 binding sites. For this study, the parent structure 1 was divided into three fragments: A (cyclohexyl), B (piperidyl) and C (phenyl). Vesamicol analogues were then selected to reflect structural modifications in these fragments. Consistent with earlier reports, vesamicol was found to exhibit nanomolar affinities at the VR and sigma 1 and sigma 2 sites, resulting in poor selectivity for the VR over the sigma sites. Vesamicol analogues characterized by an acyclic A-fragment showed moderate to low affinities at the VR and moderate to high affinities at sigma 1 and sigma 2 sites. As a result, many of these analogues showed poor selectivity for the VR. Replacement of the C4 carbon of 1 with a halobenzyl amine resulted in higher affinities at the VR coupled with moderate to low affinities at sigma 1 and sigma 2 sites. The introduction of a benzofused substituent at the C4 and C5 positions of 1 (compound 2) resulted in a 200-fold increase in affinity at the VR accompanied by a 5- to 6-fold decrease in affinity at sigma 1 and sigma 2 sites relative to the parent structure. Consequently, compound 2 showed 12,000-fold higher affinity at the VR than at sigma sites. Restricting the rotation of fragment C relative to B (by means of alkyl and alkenyl bridges) generally yielded analogues with subnanomolar affinities at the VR. The corresponding affinities of these spirofused conformationally restricted analogues were moderate to poor at sigma 1 and sigma 2 sites when fragment A was preserved. In contrast, the affinities at sigma 1 and sigma 2 sites were decreased 3- to 11-fold when fragment A was modified at position C4 and decreased up to 100-fold with benzofusion at the C4 and C5 positions of fragment A. Consequently, the spirofused analogues 15-19 were among the most selective VR ligands examined. Thus, the effect of conformational restriction in fragments A and B-C is to increase affinity at the VR while decreasing affinity at sigma 1 and sigma 2 sites, and thereby increasing selectivity for the VR over the sigma sites.

Animals↗

PubMed1984

Receptor cell responses to odorants: similarities and differences among odorants.

An extensive exploration of the discriminating properties of olfactory receptors cells has been conducted in our laboratory through the statistical processing of single cell responses recorded in the frog's olfactory epithelium. Similarities between odorant stimulating properties could be demonstrated by comparing the complex response profiles of receptor cells, resulting in the concept of odorant groups which depicts consistent relationships found between some odorous compounds. The recording technique limits the number of odorants which can be tested and compared within the same series of experiments. Thus, based upon previous studies we have chosen a specific set of 20 odorants whose characteristics are known but, up to this time, have not been compared in the same experimental system. These odorants were: acetophenone, anisole, n-butanol, DL-camphor, cyclodecanone, 1,8-cineole, p-cymene, D-citronellol, n-heptanol, isoamyl acetate, isovaleric acid, D-limonene, methyl amylketone, L-menthol, phenol, thiophenol, pyridine, thymol, cyclohexanol, cyclohexanone. The pattern of similarities between these odorants, as delineated with the aid of correlation coefficient computation, factor analysis and non-hierarchical taxonomy, confirms the reality of several odorant groups previously suggested and describes their cross-relationships. The receptor mechanisms underlying these odorant groups are discussed. Because reliable prominent features of the olfactory stimulus space can be established on an objective basis, the findings are proposed as a reference for future studies on other aspects of olfactory discrimination.

Animals↗

PubMed1986

Reduction of quantal size by vesamicol (AH5183), an inhibitor of vesicular acetylcholine storage.

Isolated unparalysed mouse phrenic nerve-hemidiaphragm preparations were indirectly stimulated in the presence of 2-(4-phenylpiperidino)cyclohexanol (AH5183, vesamicol). Spontaneous miniature endplate potentials were subsequently studied. They exhibited a large depression of amplitude which was more profound at higher stimulation frequencies and drug concentration. No post-junctional effects of the drug were observed. Since the drug blocks storage of acetylcholine by isolated synaptic vesicles, it is argued that the results support the theory of vesicular release of acetylcholine.

Acetylcholine↗

PubMed1988

Effects of an inhibitor of the synaptic vesicle acetylcholine transport system on quantal neurotransmitter release: an electrophysiological study.

The drug 2-(4-phenylpiperidino)cyclohexanol (AH5183), which potently inhibits the active transport of acetylcholine (ACh) into synaptic vesicles, was used as a pharmacological tool to study the functional role of synaptic vesicles in quantal transmitter release. Using microelectrode recording techniques, miniature endplate potentials (mepps) and nerve-evoked endplate potentials (epps) were recorded from frog cutaneous pectoris neuromuscular junctions in low Ca2+/high Mg2+ Ringer solution, and in normal Ringer with added D-tubocurarine (D-TC). Stimulation in the presence of AH5183 caused a 40% reduction in quantal size (mepp amplitude), depressed tetanic potentiation, and decreased the number of quanta released with each nerve impulse in the presence of D-TC. All of these effects appeared gradually and only after extended stimulation of the nerve, during which several hundred thousand quanta were released. Consequently, these findings suggest a serial one-time usage of vesicles, with little or no re-entry of recycled vesicles until after a large fraction of the original vesicles has been exhausted. The results primarily show that filling of synaptic vesicles with ACh is crucial for sustaining synaptic transmission, and gives further evidence that the ACh released by nerve impulses originates from these organelles.

Acetylcholine↗

PubMed1996

Evidence to suggest that cytosolic acetylcholine in rat hippocampal nerve terminals is not directly transferred into synaptic vesicles for release.

Rat hippocampal minces were loaded with [acetyl 1-14C]acetylcholine ([14C]ACh) in the presence of the "poorly penetrating" acetylcholinesterase (EC 3.1.1.7; AChE) inhibitor echothiophate and the effect of high K+ depolarization determined on the subcellular storage and release of [14C]ACh and its metabolites. Results indicated that high K+ did not augment the release of [14C]ACh. Rather, it increased the release of [14C]acetate while simultaneously reducing the level of [14C]ACh in the cytosolic (S3) fraction. When the identical experiment was performed with paraoxon, a "penetrating" AChE inhibitor, high K+ still did not increase the release of [14C]ACh. However, paraoxon prevented the K(+)-induced loss of [14C]ACh from the cytosolic fraction as well as the K(+)-induced gain of [14C]acetate in the release medium. When minces were loaded with [14C]ACh in the presence of echothiophate and subsequently subjected to high K+ depolarization in the absence or presence of vesamicol (AH5183; (-)-trans-2-[4-phenylpiperidino] cyclohexanol), a drug which blocks the refilling of synaptic vesicles with ACh, the amount of endogenous ACh released was reduced approximately 50%. Conversely, the amount of [14C]ACh released was not reduced at all. These results suggest that cytosolic ACh is not directly transported into synaptic vesicles for release when hippocampal nerve terminals are depolarized. Rather, its hydrolysis is accelerated in response to depolarization. A working hypothesis explaining the importance of the depolarization-induced breakdown of cytosolic ACh to central ACh metabolism is presented.

Acetylcholine↗

PubMed1985

Enhancement of brain [3H]flunitrazepam binding and analgesic activity of synthetic cannabimimetics.

Novel, synthetic cannabimimetics and delta 9-tetrahydrocannabinol were found to enhance the binding of [3H]flunitrazepam to mouse brain in vivo. This property, suggestive of facilitation of binding to benzodiazepine receptors, is consistent with the potentiation of the anticonvulsant activity of diazepam against pentylenetetrazol by these compounds. The relative potencies of delta 9-tetrahydrocannabinol and the new cannabimimetics for enhancing [3H]flunitrazepam binding in vivo could also be correlated with their relative analgesic efficacies. Similar pharmacological stereospecificity was displayed for both binding enhancement and analgesic effects. The following order of decreasing potency was observed: N-methyllevonantradol and (-)-CP-55,244 greater than levonantradol, canbisol, CP-42,096 and (-)-CP-55,940 greater than 9-beta-normethyl-9-beta-hydroxyhexahydrocannabinol, nabilone and CP-47,497 greater than delta 9-tetrahydrocannabinol. Dextronantradol, (+)-CP-55,940 and (+)-CP-55,244 were considerably less active than the respective (-)-enantiomers; cannabidiol was inactive. Extensive investigation of structure versus activity led to N-methyllevonantradol and the 3-(2-hydroxyphenyl)cyclohexanols derivative, (-)-CP-55,244, which are approximately 1000-fold more potent than delta 9-tetrahydrocannabinol.

Analgesics↗

PubMed1991

Local anaesthetic activity of vesamicol in the electric organ of Torpedo.

Synaptic transmission in intact pieces of the Torpedo electric organ treated with vesamicol (2-(4-phenylpiperidino)cyclohexanol, formerly AH5183) was elicited by trains of repetitive electrical stimulation at different frequencies. When the frequency of stimulation was increased from 10 to 50 or 100 Hz, micromolar concentrations of vesamicol enhanced the tetanic rundown of the successive tissue responses. This effect was already detectable with 10 microM vesamicol. It was dramatically potentiated with concentrations of 50 or 100 microM vesamicol, which caused complete failure of transmission after usually less than 10 responses. The drug was unequivocally demonstrated to act by depressing the evoked release of acetylcholine as a consequence of a highly frequency- and concentration-dependent impairment of Na+ channel function in afferent axons. It is concluded that, in the electric organ, vesamicol blocks transmission by acting as a local anaesthetic. This action of micromolar concentrations of vesamicol must be taken into account especially during high-rate nerve activity.

Acetylcholine↗

PubMed1991

Effect of AH5183 (vesamicol) on cholinergic transmission in intact airway smooth muscle.

The effect of the vesicular acetylcholine (ACh) transport blocker trans-2-(4- phenyl-piperidino)-cyclohexanol (AH5183) was studied in bronchial smooth muscle during activation of the vagus nerve. AH5183 inhibited in a dose-dependent manner the Ca(2+)-sensitive electrically induced smooth muscle contractions in vitro with a half-inhibitory concentration (IC50) of 1.6 +/- 0.4 microM. The inhibition was complete within 68 +/- 1 min (n = 8) at approximately 20 microM AH5183 and was partly reversible after washing of the preparations. AH5183 (20 microM) reduced the level of endogenous ACh by 47.4 +/- 7.6% (n = 4) during this time period. The effect of AH5183 is most likely prejunctional, since the contractions induced post-junctionally by carbachol were not altered by AH5183. The irreversible anticholinesterase, soman, increased the tonus of airway smooth muscle as a result of accumulation of spontaneously released ACh from prejunctional leakage. AH5183 had no effect on this increase of muscle contraction. The present results show that the nerve-evoked release of ACh comes from an AH5183-sensitive pool, probably a vesicular pool, whereas leakage of ACh presumably comes from the cytoplasmic pool in airway smooth muscle.

Acetylcholine↗

PubMed1985

Biochemical evidence that acetylcholine release from cholinergic nerve terminals is mostly vesicular.

The nature of the intraterminal compartments from which acetylcholine (ACh) is released following presynaptic stimulation was investigated. This was pursued by examining the effects of the anticholinergic drug 2-(4-phenylpiperidino)cyclohexanol (AH5183) on the release of newly synthesized [3H]ACh and of endogenous ACh from purified cholinergic nerve terminals (synaptosomes) which were isolated from the electric organs of Torpedo. Preincubation of the synaptosomes, with AH5183 (1-10 microM), does not affect either the intraterminal synthesis of [3H]ACh or the uptake of its precursors, but results in a marked inhibition (85%) of the release of the newly synthesized [3H]ACh. However, when AH5183 is added following the accumulation of [3H]ACh in the nerve terminals, it does not affect [3H]ACh release. AH5183 also has no effect on the release of preformed endogenous ACh. These findings, together with the previous in vitro demonstrations that AH5183 is a potent inhibitor of ACh uptake into isolated cholinergic vesicles, suggest that most of the synaptosomal ACh is secreted by a vesicular mechanism.

Acetates↗