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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

At least 271 records · Page 15Linked to original sources
PubMed1984

Synthesis and pharmacological activity of some 9-substituted delta 8-tetrahydrocannabinol analogues.

Several 9-substituted delta 8-tetrahydrocannabinol (delta 8-THC) analogues were synthesized and evaluated for biological activity in mice. Compounds with phenyl (2b) and butyl (2c) substituents were prepared by the addition of phenyllithium and n-butyllithium, respectively, to (-)-9-nor-9-oxohexahydrocannabinol (1), followed by dehydration, whereas, isopropyl (2d), PhCH2 (2e), and Ph(CH2)2 (2f) derivatives were synthesized via the Grignard reaction with subsequent dehydration. Compounds with C2H5CH(OH) (2g) and CH3CH(OH) (2h) substituents at C-9 were prepared from (-)-9-nor-9-formyl-delta 8-tetrahydrocannabinol acetate (3) by the reaction of ethyl and methyl Grignard reagents, respectively. Biological activity indicated that a methyl group at the C-9 position is, thus far, optimum for producing hypoactivity and hypothermia in mice. In addition, hydroxyethyl substitution at position 9 reduced and antinociceptive activity of delta 8-THC, in contrast to the increased activity reported for hydroxymethyl substitution.

Analgesia↗
PubMed1984

Stereoisomers of [3H]-N-allylnormetazocine bind to different sites in mouse brain.

(+)- and (-)-[3H]-N-allylnormetazocine (NANM) were synthesized and evaluated for binding to mouse brain membranes. Scatchard analysis of the saturable binding of (-)-[3H]NANM suggested a single class of binding sites with an apparent KD of 2.1 nM and an estimated maximum binding of 197 fmol/mg of protein. Increasing the concentration of Na+, K+, Mn++ or Ca++ decreased (-)-[3H]NANM specific binding. (-)-[3H]NANM apparently binds to the mu opiate receptor in that (-)-isomers, but not the (+)-isomers, of N-cis-3-chloroallylnormetazocine, N-propynylnormetazocine, pentazocine, cyclazocine, naloxone, phenazocine and morphine competed for binding. (-)-Isomers of ethylketocyclazocine, ketocyclazocine and NIH 9101 also displaced (-)-[3H]NANM binding which suggested kappa activity in addition to mu activity. Phencyclidine and its analogs did not bind to the (-)-[3H]NANM site. Scatchard analysis of saturable binding of (+)-[3H]NANM also revealed a homogeneous population of binding sites with apparent KD of 12 nM and an estimated maximum binding of 360 fmol/mg of protein. This binding site was unaffected by increasing concentrations of Na+ and K+, but binding was decreased by high concentrations of Mn++ and Ca++. The (+)-isomers of the benzomorphans N-cis-3-chloroallylnormetazocine, phenazocine, pentazocine and cyclazocine effectively displaced (+)-[3H]NANM binding. In addition, the (+)-isomers of ketocyclazocine and ethylketocyclazocine, as well as dextrorphan, a (+)-morphinan, bind to the (+)-[3H]NANM site. The (-)-isomers of mu agonist/antagonists and kappa agonists competed poorly, or not at all, for the (+)-[3H]NANM site whereas phencyclidine and related compounds exhibited a low affinity for this site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

The role of a guanine nucleotide-binding protein in the activation of rat liver plasma-membrane adenylate cyclase by forskolin.

The effects of the photoreactive GTP analogue GTP-gamma-azidoanilide on rat liver plasma-membrane adenylate cyclase are described. U.v. irradiation in the presence of the analogue abolished activation by any effector or combination of effectors that function via the activatory G protein. Partial protection against this inhibition was given by F- and guanosine 5'-[gamma-thio]triphosphate. It is concluded that GTP-gamma-azidoanilide acts by a light-induced covalent reaction with the G protein. In the dark the effects of the analogue were similar to those of GTP. Irradiation in the presence of GTP-gamma-azidoanilide was found to reduce but not to abolish activation of rat liver plasma membrane adenylate cyclase by forskolin. The activation by forskolin and GTP together were greater than the sum of the individual activations. Forskolin doubled adenylate cyclase activity in the presence of glucagon and guanosine 5'-[beta, gamma-imido]triphosphate, which might be expected to activate to the maximum possible extent via the G protein. It is concluded that there are two components to the forskolin activation, a guanine nucleotide-dependent and a guanine nucleotide-independent component.

Adenosine Triphosphate↗
PubMed1983

The role of GTP in prostaglandin E1 stimulation of adenylate cyclase in platelet membranes.

Adenylate cyclase activity in platelet membrane preparations was measured in the presence of prostaglandin E1 (PGE1), GTP and a non-hydrolysable analogue of GDP, guanosine 5'-[beta-thio]diphosphate (GDP[beta S]). A dose-dependent inhibition of adenylate cyclase by GDP[beta S] was observed that could be reversed either by adding increased amounts of GTP or of PGE1.

Adenylyl Cyclase Inhibitors↗
PubMed1983

Interactions between phencyclidine and delta 9-tetrahydrocannabinol in mice following smoke exposure.

The behavioral and pharmacological interactions between delta 9-tetrahydrocannabinol (delta 9-THC) and phencyclidine (PCP) were studied following coadministration of the drugs in smoke to mice. While delta 9-THC (25, 50 or 100 mg/cigarette) had little effect on spontaneous motor activity, all doses attenuated the hyperactivity elicited by PCP X HCl (25 and 50 mg/cigarette). delta 9-THC produced a dose-related hypothermia. PCP X HCl (50 mg/cigarette) had no effect on body temperature but enhanced hypothermia when combined with 25 mg of delta 9-THC. delta 9-THC (100 mg/cigarette) had no effect on the biodisposition of 3H-PCP and its pyrolytic product, 3H-phenylcyclohexene (3H-PC), when examined immediately after 3H-PCP X HCl (50 mg/ cigarette) exposure. At 30 min, brain, liver, lung and plasma contained higher concentrations of 3H-PC and fat and plasma contained lower concentrations of 3H-PCP in the mice exposed to both drugs compared to 3H-PCP X HCl alone. It appears, therefore, that delta 9-THC has the potential for altering the behavioral, pharmacological and pharmacokinetic sequelae of PCP abuse.

Adipose Tissue↗
PubMed1983

Antinociceptive action of nicotine and its methiodide derivatives in mice and rats.

Three quaternary methiodides of nicotine were prepared and tested for antinociceptive activity in the mouse tail-flick, mouse phenylquinone and rat tail-flick tests. Following peripheral administration, all three methiodides were inactive in the mouse and rat tail-flick procedures, whereas nicotine was active in both tests, which suggested that nicotine was acting centrally. Quaternization of nicotine did not eliminate antinociceptive activity as demonstrated by the intraventricular injection of the methiodides in mice. Nicotine pyrrolidine and bis methiodides were somewhat more potent than nicotine, whereas nicotine pyridine methiodide was considerably less potent than nicotine in the tail-flick procedure. Systemically administered nicotine pyrrolidine methiodine was approximately one-third as active as nicotine in the mouse phenylquinone test; nicotine pyridine methiodide and nicotine bis methiodide were 100 and 300 times less active, respectively. Hexamethonium partially blocked nicotine and nicotine pyrrolidine methiodide, whereas mecamylamine blocked nicotine completely but nicotine pyrrolidine methiodide partially. Nicotine may have both central and peripheral actions in the mouse phenylquinone test, whereas nicotine pyrrolidine methiodide may have both nicotine and non-nicotine like antinociceptive activity. The radiolabelled methiodides were synthesized and their disposition in body tissues studied. The methiodides were found to penetrate brain poorly (plasma-to-brain ratios greater than 20). The methiodides were metabolized to nicotine to a small extent. This metabolism occurred to a greater extent in mice than in rats.

Analgesics↗
PubMed1983

Disposition of phencyclidine and its pyrolytic products in mice exposed to smoke.

Phencyclidine (PCP) is a drug that is frequently misused by smoking. Recent popularity of PCP abuse by this method probably stems from the fact that smoking allows users to titrate themselves as well as reduce the incidence of adverse reactions. PCP is pyrolyzed at high temperatures to form predominantly 1-phenyl-1-cyclohexene (PC). Piperidine and related products are formed in smaller quantities. Smoke from cigarettes impregnated with PCP contains approximately equimolar concentrations of PCP and PC. It has been shown that PCP and PC are present in the circulation of individuals after they smoke PCP-laden cigarettes. In addition, PCP and PC can be found in plasma as well as in all major organs of mice exposed to smoke from PCP-containing cigarettes. The brain concentrations of PC in mice are comparable to those of PCP immediately after exposure but the PC levels decline somewhat more rapidly. Actually the time course of behavioral activity correlates better with PCP levels than with PC levels. In addition, PC and its major metabolites, as well as piperidine, are considerably less active behaviorally than PCP, which suggests that pyrolysis represents an inactivation process for PCP. However, a total lack of contribution of pyrolysis products to PCP's actions has not been ruled out.

Animals↗
PubMed1983

Relationship of the biodisposition of the stereoisomers of nicotine in the central nervous system to their pharmacological actions.

The stereoisomers of nicotine were evaluated for their effectiveness in producing antinociception and altering spontaneous activity and Rotarod performance in rats. (-)-Nicotine was found to be 6, 15 and 30 times more active than its unnatural enantiomer, (+)-nicotine, in the spontaneous activity, Rotarod and antinociceptive tests, respectively. Biodispositional studies revealed that the time course (-)-[3H]nicotine closely paralleled the time course of effects on spontaneous activity and Rotarod performance but not antinociception, which suggested that multiple mechanisms were involved in the actions of nicotine. In addition, the distribution studies showed the brain and plasma levels of (-)-[3H]nicotine were higher than those of (+)-[3H] nicotine, which indicate that the pharmacological stereoselectivity of nicotine is less than originally determined. Finally, the greatest difference in the regional localization in brain of the stereoisomers was found in cerebral cortex, hippocampus and corpus striatum.

Analgesia↗
PubMed1982

The effect of beta-adrenergic agonists on the membrane potential of fat-cell mitochondria in situ.

1. The accumulation of [3H]methyltriphenylphosphonium by isolated fat-cells was used to estimate the membrane potential of mitochondria in situ. 2. Adrenaline caused a large decrease in the accumulation of [3H]methyltriphenylphosphonium. Mitochondria in fat-cells incubated in the presence of adrenaline had a very low calculated membrane potential. This effect was also given by isoprenaline (a beta-adrenergic agonist) and was blocked by propranolol (a beta-adrenergic antagonist). 3. The effect of isoprenaline could be partially antagonized by the use of media with high albumin concentrations. Addition of sodium oleate to saturate the fatty acid-binding sites on the albumin reversed this antagonism. 4. It is proposed that the decrease in the calculated mitochondrial membrane potential is due to the uncoupling effect of the non-esterified fatty acids released by the stimulation of lipolysis observed in the presence of beta-adrenergic agonists.

Adipose Tissue↗
PubMed1982

The effect of alpha-adrenergic agonists on the membrane potential of fat-cell mitochondria in situ.

1. The accumulation of [3H]methyltriphenylphosphonium by isolated fat-cells was used to estimate the membrane potential of mitochondria in situ. 2. An alpha-adrenergic receptor-mediated decrease in the apparent accumulation of [3H]methyltriphenylphosphonium was observed. Methoxamine, clonidine and low concentrations of phenylephrine decreased the calculated mitochrondrial membrane potential without significantly raising cyclic AMP levels, adenylate cyclase activity or stimulating lipolysis. The agonist potency order was phenylephrine greater than methoxamine greater than clonidine. 3. The decrease in the calculated mitochondrial membrane potential caused by phenylephrine, clonidine and methoxamine was blocked by the alpha-adrenergic antagonist prazosin but not by yohimbine nor by the beta-antagonist propranolol. This suggests that the effect on the calculated mitochondrial membrane potential may be mediated by alpha 1-like receptors.

Adipose Tissue↗
PubMed1982

Pharmacological activity and toxicity of phencyclidine (PCP) and phenylcyclohexene (PC), a pyrolysis product.

Initial acute behavioral studies in mice indicated that phencyclidine (PCP) produced marked motor impairment as measured by the inverted screen technique with an ED50 value of 4.1 muMole/kg (i.v.). Phenylcyclohexene (PC) was considerably less active with an ED50 value of 325 muMole/kg (i.v.). PCP was also shown to be more lethal than PC as acute (24 hr; i.v. injection) LD50 values (muMoles/kg) in males were 57 and 448, and in females were /6 and 425, respectively. A greater acute lethality was also produced by PCP after i.p. and p.o. administration. Subchronic (14-day) exposure (i.p.) to PCP at doses up to approximately 40 percent of the acute LD50 value (123.6 muMole/kg, i.p., daily) was without significant effect on body and organ weights, hematology and clinical chemistry, and humoral and cell-mediated immunity. Higher doses of PCP were not possible because of acute lethality. Subchronic exposure to PC (63.4, 317, and 634.5 muMoles/kg; 4 percent, 20 percent and 40 percent of acute i.p. LD50 value, respectively) produced several marked effects. At the highest dose tested, body weight and thymus weight in both males and females, and liver weight in males were significantly decreased. The spleen weight of males exposed to 317 muMole/kg PC was also significantly decreased. Humoral immunity (production of antibody forming cells) was significantly inhibited in both males and females exposed to PC. In contrast, cell-mediated immunity (development of a delayed-type hypersensitivity response) was only significantly inhibited in females. As PCP has no measurable toxicity under these conditions and PC produced significant effects at relatively high doses, the results suggest that neither chemical is exceptionally toxic following subchronic exposure.

Animals↗
PubMed1982

Local anaesthetics including benzyl alcohol activate the adenylate cyclase in Trypanosoma brucei by a calcium-dependent mechanism.

1. The adenylate cyclase of Trypanosoma brucei is activated by local anaesthetics. 2. Activation of adenylate cyclase by the local anaesthetic, benzyl alcohol, requires Ca2+. 3. The kinetics of the presteady state reveal that the activation step occurs prior to and is separate from the catalytic step. 4. The activation step in the presence of Ca2+ can be stimulated some 200-fold and is highly co-operative with respect to benzyl alcohol concentration. 5. The mechanism by which local anaesthetics activate may be by exposing the Ca2+ -binding site of the Ca2+ receptor which is oriented towards the hydrophobic regions of the plasma membrane in the basal state.

Adenylyl Cyclases↗
PubMed1982

3'-Hydroxy- and (+/-)-3',11-dihydroxy-delta 9-tetrahydrocannabinol: biologically active metabolites of delta 9-tetrahydrocannabinol.

Synthesis of 3'-hydroxy- (7) and (+/-)-3',11-dihydroxy-delta 9-tetrahydrocannabinol (11), metabolites of delta 9-THC, is described. Condensation of the monoterpene (+/-)-cis-p-menth-2-ene-1,8-diol (1) and (+/-)-3'-acetoxyolivetol (2) in the presence of fused ZnCl2 in CH2Cl2 gave a mixture from which the delta 9-THC derivative 3, containing small amounts of the delta 8-isomer 4, was isolated after column chromatography. This mixture was separated as their diacetates 5 and 6 by high-pressure liquid chromatography. Alkaline hydrolysis (5% KOH in MeOH) of 5 furnished the metabolite 7. Condensation of (+/-)-8 with 2 in the presence of p-toluenesulfonic acid gave 9a, which was acetylated to 9b. Treatment with HgO/BF3 X Et2O in wet THF gave the aldehyde 10. Reduction with LiAlH4 furnished the metabolite 11. These metabolites were compared with delta 9-THC for their ability to depress spontaneous activity and rectal temperature in mice and for their effects on overt behavior in dogs. 3'-Hydroxy-delta 9-THC was also compared to delta 9-THC in the mouse sympatomatology test and cardiovascular system in dogs. The metabolites produced pharmacological effects similar to those of delta 9-THC in all tests. 3'-Hydroxy-delta 9-THC was 2-3 times more effective than delta 9-THC in the behavioral tests, whereas (+/-)-3',11-dihydroxy-delta 9-THC was approximately 3 times less active than delta 9-THC.

Animals↗
PubMed1982

Distribution of radioactivity in the spinal cord after intracerebroventricular and intravenous injection of radiolabeled opioid peptides in mice.

The rejection of [beta-125I]endorphin and D-[3H]Ala2-Met-enkephalinamide into the lateral ventricles of mice revealed that radioactivity could be transported rapidly via the cerebrospinal fluid (CSF) down to the lowest part of the spinal cord. The maximal levels of both compounds in thoracic, lumbar and sacral sections of the spinal cord occurred 10 min after administration, which coincided with the peak antinociceptive action of morphine after i.c.v. administration. When [3H]Leu-enkephalin was administered i.c.v., the level of radioactivity in the spinal cord did not increase with time and these levels in spinal cord were considerably lower than those of either [beta125I]endorphin or D-[3H]Ala2-Met-enkephalinamide. This difference in distribution of these compounds, coupled with the observation that [beta-125I] endorphin and D-[3H]Ala2-Met-enkephalinamide were more stable than [3H]Leu-enkephalin in CSF, suggested that radioactivity in the spinal cord of mice treated with [beta-125I]endorphin or D-[3H]Ala2-Met-enkephalinamide was due to unchanged material. Very low levels of radioactivity were found in brain or spinal cord after i.v. administration of either [beta-125I]endorphin or D-[3H]Ala2-Met-enkephalinamide. This latter observation supports the view that endorphins administered i.c.v. enter the spinal cord directly through CSF rather than reentry from the general circulation. The results presented herein support the hypothesis that the antinociceptive action of morphine in mice as measured by the tail-flick procedure can be mediated via the release of endogenous compound(s) from brain into CSF which are transported to lower sections of the spinal cord where they inhibit the tail-flick response.

Analgesics↗