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Biomedical subjects

D R Compton

Publications and source records attributed to D R Compton.

49 records · Page 3Linked to original sources
PubMed1990

Cannabis dependence and tolerance production.

The chronic abuse of many drugs produces both marked tolerance and physical dependence. Marked tolerance to cannabis has been observed in experimental animals and humans. However, reports of physical dependence, as characterized by significant withdrawal symptomatology upon cessation of chronic cannabis exposure, has not been well established or clearly defined in any species. The abuse potential of cannabis is more readily observed in humans than in experimental animal investigations. This may be due to the physiochemical characteristics of cannabis or delta 9-THC, which complicates this type of animal experimentation. It is more likely that the greatest dangers of cannabis abuse involve the pharmacological effects of the drug upon the central nervous system and other organs, rather than the development of dependence.

Animals↗
PubMed1990

Characterization of the lipophilicity of natural and synthetic analogs of delta 9-tetrahydrocannabinol and its relationship to pharmacological potency.

delta 9-Tetrahydrocannabinol, the primary psychoactive constituent in marihuana, has been studied extensively for the last 20 years; however, the mechanisms responsible for cannabinoid activity in the central nervous system are not well understood. Although it is thought that lipophilicity plays an important role in the actions of cannabinoids, studies have not been conducted to determine whether a relationship exists between the lipophilicity and behavioral potency of cannabinoid analogs. Two procedures were used to obtain n-octanol/water partition coefficients (Po/w) of naturally occurring and synthetic cannabinoids: reverse-phase high-pressure liquid chromatographic estimation of Po/w and computer calculation of Po/w based on molecular structure. The Po/w value for delta 9-tetrahydrocannabinol obtained in this study, 9.44 x 10(6), is much greater than previously reported values obtained using shake-flask methodology, yet it is in agreement with the computer calculation based on molecular structure or molecular volume. The lipophilicity of the analogs determined in this study ranged from Po/w values of 3.92 x 10(2) to 1.93 x 10(11). All pharmacologically active cannabinoid compounds were extremely lipophilic (log Po/w values greater than 4.5). Several structural alterations were found to exert considerable influence on the lipophilicity of cannabinoid analogs. Increasing the length of the side chain in a homologous series of analogs results in an increase in lipophilicity of approximately 3-fold for each CH2 group added. Introduction of a single hydroxyl group decreased lipophilicity 3- to 40-fold, depending on the site of attachment. The behavioral potency of active analogs was not found to be correlated to lipophilicity. Therefore, data obtained in this study suggest that lipophilicity is a component, but not a primary determinant of pharmacological activity in the cannabinoids.

Animals↗
PubMed1990

Investigation of the role of the phenolic hydroxyl in cannabinoid activity.

Structure-activity relationship studies have suggested that the phenolic hydroxyl group is essential for the pharmacological activity of the cannabinoids. However, it remains to be established whether it is the hydrogen of the phenolic hydroxyl that is important (possibly because this hydrogen can participate in a hydrogen bonding interaction) or whether it is the oxygen of the phenolic hydroxyl that is important (possibly because one of the lone pairs of electrons in this oxygen can serve as a hydrogen bond acceptor). Two new etherified cannabinoids were prepared in which the phenolic hydroxyl oxygen is incorporated into a fourth ring. These new compounds were designed to test the importance both of the phenolic hydroxyl oxygen and of the orientation of its lone pairs of electrons for cannabinoid pharmacological activity. O,2-Propano-delta 8-tetrahydrocannabinol (0,2-Propano-delta 8-THC) was designed to mimic delta 9-THC in its phenol conformation I (C2-C1-O-H = 7 degrees). O,10-Methano-delta 9-tetrahydro-cannabinol (0,10-Methano-delta 9-THC) was designed to mimic delta 9-THC in its phenol conformation II (C2-C1-O-H = 167 degrees). Molecular mechanics calculations revealed that 1) there are two accessible minimum energy conformers for O,2-propano-delta 8-THC, which differ principally in the conformation of the new fourth ring, and 2) there are three accessible minimum energy conformers for O,10-methano-delta 9-THC, the first two of which differ mainly in the conformation of the new fourth ring, whereas the third possesses an alternate pyran ring conformation. Wave functions and molecular electrostatic potential (MEP) maps were calculated for each accessible conformer of O,2-propano-delta 8-THC and of O,10-methano-delta 9-THC. The resultant MEP maps compared well with the corresponding MEP maps generated for delta 9-THC in each of its two minimum energy conformations (two phenolic hydroxyl positions). These results imply that 1) O,2-propano-delta 8-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation 1 and 2) O,10-methano-delta 9-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation II. Pharmacological evaluation of the analogs revealed that O,10-methano-delta 9-THC was inactive in all mouse tests, as well as the rat drug discrimination model. O,2-Propano-delta 8-THC was similar to delta 8-THC in that it depressed rectal temperature and produced antinociception and ring immobility in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Stereochemical effects of 11-OH-delta 8-THC-dimethylheptyl in mice and dogs.

The effects of the enantiomers of 11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (11-OH-delta 8-THC-DMH) on spontaneous activity, rectal temperature, tail-flick latency, and catalepsy were studied in mice and in the dog static-ataxia model to determine the relative potency of each enantiomer. The (-)-enantiomer was active in all tests between 3-100 micrograms/kg, while the (+)-enantiomer was inactive at 30 mg/kg in the mouse and 1 mg/kg in the dog. The (-)-enantiomer was 100-800 times more potent than delta 9-THC in the mouse. The high degree of enantioselectivity and potency are suggestive of an interaction at a specific site such as a receptor.

Animals↗
PubMed1989

Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens.

The purpose of this investigation was to determine if striatal or nucleus accumbens dopamine (DA) release, ACh release or DA receptor function were altered by acute and chronic haloperidol or clozapine treatment in a manner consistent with the reported pharmacological effects of each drug on A9 and A10 DA cell bodies and projection areas, when experiments were performed without a drug-free, or washout, period after drug treatment. The release of neurotransmitters reported here was evaluated using a slice-superfusion assay system. Transmitter release was induced either by an electrical field (for DA and ACh) or by application of either amphetamine or amfonelic acid (DA only). Dopaminergic receptor function was assessed by inhibiting electrically stimulated ACh release with in vitro TL-99 (a dopaminergic agonist) and by reversing that inhibition with in vitro neuroleptics or with ex vivo experimental paradigms (the in vitro analysis of transmitter release subsequent to in vivo drug administration). These data suggest that although there are differences between haloperidol and clozapine, there is no difference between the degree of postsynaptic DA receptor blockade produced that can be attributed to the duration of neuroleptic treatment. Chronic clozapine (20 mg/kg x 21 days) reversed TL-99-induced inhibition of ACh release in the nucleus accumbens only, whereas chronic haloperidol (0.5 mg/kg x 21 days) produced a similar reversal in both brain areas. One possible explanation for the lack of effect of chronic clozapine treatment in the striatum is that carrier-mediated (amphetamine-stimulated) DA release is enhanced in the striatum but not in the nucleus accumbens, suggesting that the potential DA receptor block in the striatum may be compromised by enhanced striatal DA levels. Acute haloperidol (0.5 mg/kg) was found to increase electrically stimulated ACh release in the striatum and DA release in the nucleus accumbens. Tolerance developed in the striatum, but not the nucleus accumbens, with repeated administration. However, acute clozapine had no effect on ACh release in either area, but it was found to enhance DA release in the striatum, an effect to which tolerance developed with chronic administration. Further, comparison of these data with data obtained using haloperidol and clozapine in vitro suggests that it is unlikely that these effects are due to residual drug still present in these tissues at the time of experimentation. These data are discussed with regard to electrophysiological and pharmacological differences observed between clozapine and haloperidol on the activity of A9 and A10 DA cells after chronic neuroleptic treatment.

Acetylcholine↗
PubMed1988

Modification of phencyclidine intoxification and biodisposition by charcoal and other treatments.

Studies were conducted to determine whether single or combination treatments of charcoal, paraffin, cholestyramine, and/or ammonium chloride (NH4Cl), would alter the rotarod-measured motor dysfunction induced by 10 to 90 mg/kg of phencyclidine (PCP). Additionally, the effect of NH4Cl/charcoal treatment of the biodisposition of 50 mg/kg PCP was evaluated in order to assess whether amelioration of behavioral effects could be correlated to alterations in brain levels, plasma levels, and/or the renal clearance of PCP and metabolites. NH4Cl/charcoal treatment proved more effective at reducing intoxication than either treatment singly, though effectiveness was reduced by larger doses of PCP. NH4Cl/charcoal treatment reduced intoxification by 40, 16, and 21% at PCP doses of 10, 25, and 50 mg/kg. However, the reduction in motor dysfunction observed at 25 and 50 mg/kg PCP was greater than the sum of the individual treatments. In contrast, the effect of combined NH4Cl and charcoal treatment on the biodisposition of 50 mg/kg PCP is not synergistic, but appears instead to be due simply to the additive effects of the individual treatments. Thus the amelioration of PCP intoxication cannot be fully explained by alterations in PCP biodisposition.

Ammonium Chloride↗
PubMed1988

Pharmacology and stereoselectivity of structurally novel cannabinoids in mice.

The pharmacological effects of three stereoisomeric pairs of structurally novel cannabinoids were tested after i.v. administration in mice for depression of spontaneous activity and the production of hypothermia, antinociception and catalepsy. The (-)-enantiomers were as much as 770 times more potent than delta 9-6a,10a-trans-tetrahydrocannabinol and were 7 to 2000 times more potent than their respective (+)-enantiomers. The order of potency for cannabinoid-induced effects was spontaneous activity greater than antinociception greater than hypothermia greater than or equal to catalepsy. Levonantradol was active between 0.123 to 1.5 mg/kg, whereas dextronantradol, its (+)-enantiomer was inactive. (-)-CP 55,244 and (-)-CP55,940 analogs which lack the dihydropyran ring were 5 to 775 times more potent than delta 9-6a,10a-trans-tetrahydrocannabinol and 30 to 2000 times more potent than their respective (+)-enantiomers. Some separation of effects was demonstrated with (+)-CP 55,243 and (-)-CP 56,667 which were inactive in producing hypothermia and catalepsy but were active in the spontaneous activity and tail-flick procedures. The high degree of enantioselectivity and potency of these nonclassical cannabinoids are indicative of a highly specific mechanism of action such as a receptor.

Adenylyl Cyclases↗
PubMed1987

(+)- and (-)-N-allylnormetazocine binding sites in mouse brain: in vitro and in vivo characterization and regional distribution.

In vivo and in vitro binding studies, both in whole brain and in selected areas, indicate that non-identical (+)- and (-)-NANM sites exist in the mouse brain, and each exhibits a different regional distribution. The in vivo binding of (+)-3H-NANM was found to be saturable at pharmacologically relevant doses, and represents a relatively small (10-22%) portion of total brain (+)-3H-NANM concentrations. The in vivo binding of (+)-3H-NANM was selectively displaced by (+)-NANM and PCP, and more sensitive to haloperidol and (+)-ketocyclazocine than the (-)-3H-NANM site. The in vivo binding of (-)-3H-NANM was selectively displaced by (-)-NANM, and more sensitive to naloxone and (-) ketocyclazocine than the (+)-3H-NANM site, and insensitive to PCP. This study indicates that the investigation of NANM binding sites is possible using in vivo binding techniques, and that each isomer apparently binds, in the mouse brain, to a single class of distinct sites.

Animals↗
PubMed1987

Pharmacological evaluation of agonistic and antagonistic activity of cannabinoids.

The behavioral effects of cannabinoids are dependent upon numerous variables which include species differences, dose, experimental conditions, etc. The complexity of the cannabinoid behavioral syndrome certainly complicates attempts to establish biochemical correlates. It is for this reason that attempts are being made to develop analogs that exhibit selective behavioral effects. The pharmacological profile of the analogs that exhibit selective behavioral effects. The pharmacological profile of the analogs summarized in table 6 suggests a tentative classification for the cannabinoids. While there are numerous analogs which produce the entire spectrum of cannabinoid effects, only those discussed within this article are grouped in class 1. CBD and many of its analogs appear to be devoid of cannabinoid effects, but they are capable of producing CNS depression at large doses (class 2). It is our working hypothesis that the compounds in class 2 may be altering membrane peturbation in a nonspecific fashion. This latter effect may or may not be related to the psychoactive cannabinoids. Class 3 compounds are potent CNS depressants that appear to lack other effects that are unique to cannabinoids. These analogs are particularly interesting in that they may be altering membrane function i a specific fashion in contrast to nonspecific effects exerted by analogs in class 2. Analogs in class 4 appear to exert selective CNS depression. While the mechanism by which these analogs are producing their effects may be proven to be different from those postulated, it does appear that a classification of cannabinoid effects is possible through structural alterations in the cannabinoid molecule.

Analgesics↗
PubMed1985

Striatal synaptosomal dopamine synthesis: evidence against direct regulation by an autoreceptor mechanism.

Regulation of the rate-limiting step in dopamine (DA) synthesis was estimated in striatal synaptosomes by measuring the rate of hydroxylation of L-4-[3H]phenylalanine, a substrate of tyrosine hydroxylase (TH). DA inhibited hydroxylation with an IC50 of 0.2 microM. The concentration-response curve of DA-induced inhibition was not affected by the presence of 1 microM chlorpromazine, a phenothiazine DA antagonist. Sulpiride and haloperidol, DA antagonists of the benzamide and butyrophenone classes respectively, also failed to alter the inhibition of substrate hydroxylation by 1 microM DA, even at concentrations up to 10 microM. In contrast, a parallel 15 fold shift to the right in the concentration-response curve of DA-induced inhibition of hydroxylation was obtained when 10 microM nomifensine, a competitive DA uptake inhibitor, was added. Even in the presence of nomifensine, 1 microM chlorpromazine had no effect on the DA concentration-response curve. The addition of DMPH4, an artificial cofactor for TH, completely blocked DA-induced inhibition of enzymatic activity. These data suggest that direct autoreceptor control of synaptosomal TH activity does not exist in vitro, and that DA-induced inhibition of TH occurs subsequent to reuptake via classical feedback inhibition, presumably by competitive displacement of the necessary endogenous cofactor.

Animals↗
PubMed1983

Regulation of bacterial glycogen synthesis. Stimulation of glycogen synthesis by endogenous and exogenous cyclic adenosine 3':5'-monophosphate in Escherichia coli and the requirement for a functional CRP gene.

In Escherichia coli cya mutants, deficient in adenylate cyclase (EC 4.6.1.1), basal cellular rates of glycogen synthesis were lower and the relative increases produced by exogenous cyclic adenosine 3',5'-monophosphate during growth on glucose were greater than in their respective parent strains. These observations provide strong evidence that endogenous cyclic AMP is one of the key regulators of glycogen synthesis in growing E. coli. In crp mutants, deficient in cyclic AMP receptor protein (CRP), the basal cellular rates of glycogen synthesis were much lower than in their respective parent strains. Stimulation of glycogen synthesis by exogenous cyclic AMP was markedly attenuated in the three crp mutants. Thus, stimulation of glycogen synthesis by either endogenous or exogenous cyclic AMP appears to require CRP. Functional CRP appeared to be required for all three responses observed after cyclic AMP addition: an abrupt step-up in the cellular rate of glycogen synthesis, a continuing exponential increase in rate, and a stimulation of the rate during a subsequent nitrogen starvation. To account for these responses, we derived a mathematical model in which the cyclic AMP-CRP complex regulates the differential rate of synthesis of an enzyme metabolizing an effector of the rate-limiting enzyme of glycogen synthesis.

Cyclic AMP↗
PubMed1983

Free-radical inhibition of ATPase in hamster cheek pouch homogenates.

The effects of free-radicals generated by either the oxidation of hypoxanthine by xanthine oxidase (HX/XO) or the lipoxidation of arachidonic acid (AA) on the ATPase of the hamster cheek pouch has been studied. Cheek pouches were removed from female golden syrian hamsters and homogenized. ATPase activity was measured by the production of Pi at 37 degrees. HX/XO and AA were added at a final concentration of 9.6 X 10(-5) M HX with 5 X 10(-2) units HX and 5 X 10(-5) M AA with and without 1 X 10(-4) M ouabain. HX/XO produced a 24.7% inhibition alone and 35.0% when combined with ouabain. Ouabain alone produced a 7.1% inhibition. AA produced a 23.6% inhibition alone and 24.3% inhibition when combined with ouabain. Ouabain alone produced a 5.4% inhibition in this series. When AA was added in doses ranging from 1 X 10(-5) to 2 X 10(-3) M, a plot of percent inhibition versus log dose followed a typical sigmoid type curve. The IC50 was 1.5 X 10(-4) M. These results suggest that free-radicals are capable of inhibiting the ATPase found in the hamster cheek pouch tissues. The possible modes of action of the free-radicals in producing this inhibition are discussed.

Adenosine Triphosphatases↗