B. Kenneth Koe

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.

Sertraline, a selective inhibitor of serotonin uptake, induces subsensitivity of β-adrenoceptor system of rat brain

Subacute administration (b.i.d. for 4 days) of sertraline, a potent and selective inhibitor of serotonin uptake, was found to reduce cyclic AMP generation by the norepinephrine receptor-coupled adenylate cyclase in rat limbic forebrain slices and decrease the number of beta-adrenoceptors in rat cerebral cortex without affecting the affinity of [3H]dihydroalprenolol binding. Co-administration of sertraline and the serotonin agonist, quipazine, at doses at which neither agent had an effect, resulted in desensitization of norepinephrine receptor-coupled adenylate cyclase and down-regulation of beta-adrenoceptors. These findings suggest that increased serotonergic activity may be involved in the induction of subsensitivity of the beta-adrenoceptor system of rat brain by sertraline.

[3H]Ro 15-1788 binding to benzodiazepine receptors in mouse brain in vivo: marked enhancement by GABA agonists and other CNS drugs

Administration of the benzodiazepine receptor antagonist, [3H]Ro 15-1788, to mice intravenously was found to label these receptors in brain. Binding of [3H]Ro 15-1788 in vivo was strongly blocked by pretreating mice with clonazepam or diazepam. Marked enhancement of [3H]Ro 15-1788 binding in vivo was induced by progabide or sodium valproate. This effect was greater than a similar enhancement of [3H]flunitrazepam binding. The increased membrane-bound [3H]Ro 15-1788 elicited by progabide was completely dissociated on subsequent incubation with Ro 15-1788, diazepam or clobazam, indicating that the enhanced binding occurred at benzodiazepine receptors. Compounds that exert diazepam-like actions and/or indirect GABAergic activity (cartazolate, pentobarbital, methaqualone, levonantradol, phenytoin) elicited enhancement of [3H]Ro 15-1788 in vivo. Other CNS agents (atypical neuroleptics, GABA antagonists, baclofen, some 5-HT1 agonists) also induced elevation of [3H]Ro 15-1788 binding in vivo, as did drugs exerting vasodilatatory effects (papaverine, nimodipine, verapamil, prazosin, N6-cyclohexyladenosine). Possible explanations for enhancement of [3H]Ro 15-1788 binding in vivo include increase in the number of benzodiazepine receptors induced by GABA or GABAergic drugs or effects of binding enhancers that elevate brain levels of [3H]Ro 15-1788, such as accelerating cerebral blood flow, competing for radioligand binding sites in plasma or increasing metabolic stability of the radioligand.

(+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine binding to σ receptors in mouse brain in vivo

Binding of i.v. administered (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]3-PPP) in the brain of intact mice is antagonized dose responsively by σ receptor ligands. The correlation of potencies for inhibition of binding in vivo and in vitro indicates that σ receptors in mouse brain are labeled in vivo by i.v. [3H]3-PPP. 3-PPPP, the N-phenylpropyl derivative of norpropyl-3-PPP exhibits very high affinity for σ receptors in vitro and in vivo.

GABA‐like Actions of Levonantradol

Abstract: The interaction of levonantradol and its pharmacologically less active (+)‐enantiomer with GABAergic mechanisms was studied in several in vivo systems: (1) rat cerebellar cGMP, based on the inverse relationship of GABAergic activity and cGMP levels; (2) convulsions elicited by 3‐mercaptopropionic acid, an inhibitor of GABA synthesis; and (3) activated dopamine synthesis in rat striatum following blockade of dopamine receptors. Levonantradol decreased rat cerebellar cGMP content at low doses (1.0 mg/kg intraperitoneally) and antagonized elevation of cGMP levels by the GABA biosynthesis inhibitor isoniazid at even lower doses (0.32 mg/kg intraperitoneally); this activity pattern is suggestive of GABAergic activity. This conclusion is also supported by levonantradols protection of mice against the convulsant effects of 3‐mercaptopropionic acid. GABAergic agents are known to antagonize the enhanced dopamine synthesis and turnover that accompany dopamine receptor blockade by neuroleptics. Levonantradol (0.047 mg/kg intravenously) stereospecifically attenuated the elevated dopa accumulation induced by haloperidol. Levonantradol is at least 100‐fold more active than THC in blocking isoniazid‐induced elevation of cGMP levels in rat cerebellum or haloperidol‐induced enhanced dopa accumulation in rat striatum.

Facilitation of Benzodiazepine Binding by Levonantradol

Abstract: Levonantradol enhanced binding of 3H‐diazepam to rat cortical membranes. Scatchard analysis of this effect showed apparent KD and Bmax changes at 100 μM levonantradol and a KD decrease at 50 μM. Dextronantradol caused a similar enhancement, suggesting a lack of stereospecificity in vitro. Subsequently, levonantradol at pharmacologic doses (0.15 mg/kg subcutaneously) was found to enhance the binding of intravenous 3H‐flunitrazepam to mouse brain. In contrast to the results in vitro, dextronantradol showed no enhancement of 3H‐flunitrazepam binding at doses up to 15 mg/kg subcutaneously. This stereospecific interaction with benzodiazepine receptors in vivo suggests that levonantradol may facilitate the pharmacologic actions of benzodiazepines. Levonantradol, at doses of 0.32 and 3.2 mg/kg subcutaneously, which did not block the convulsant effect of pentylenetetrazol, enhanced both the potency and efficacy of diazepam in elevating the absolute threshold of pentylenetetrazol for eliciting clonic seizures. Consistent with its lack of facilitation of benzodiazepine binding, dextronantradol at 3.2 mg/kg, a dose without effect on pentylenetetrazol‐induced convulsions, showed little or no enhancement of diazepams anticonvulsant activity against the latter.

Chapter 5. Adaptive Changes in Central Nervous System Receptor Systems

Publisher Summary This chapter discusses the recent literature on adaptive changes in central norepinephrine (NE), serotonin (5-HT), and dopamine (DA) receptor systems and concentrates on the drug-induced effects that could relate to the therapeutic modes of action in human diseases. The chapter discusses the reviews of the topics associated with the central nervous system (CNS) receptor systems. A rapid and reversible desensitization and down-regulation of the β-receptors of rat cerebral cortex is observed on the incubation of tissue slices with isoproterenol or desipramine (DMI), an NE uptake blocker. Similar adaptive changes in the receptors of the NE system also occur in vivo in the brain when NE levels are altered. Depression is a CNS disease is believed to be associated with a perturbation of central NE transmission. The first effective drugs in depression were monoamine oxidase (MAO) inhibitors and tricyclic uptake blockers that increase the concentration of neuronal or synaptic NE, respectively. Administration of multiple daily doses of drug produces down-regulation faster than single daily dosing and allows a lower dose per injection. In a time course study in rats, DMI (10 mg/kg b.i.d.) elicited maximal desensitization of cyclic AMP (cAMP) accumulation by isoproterenol in cortical slices in 5 to 7 days and down-regulation of β-adrenoceptors in cortical membranes after seven days. The role of serotonergic changes in depression and anti-depressant therapy has been a subject of intense study. For example, brains of suicide victims exhibited an increase in cortical 5-HT 2 binding sites; either an increase or a decrease in 3 [H]imipramine binding.

Contrasting locomotor effects of catecholamine releasers and tyrosine hydroxylase inhibitors in MAO-inhibited mice

SummaryThe tyrosine hydroxylase inhibitors l-α-methyltyrosine (α-MT) and m-iodo-l-α-methyltyrosine (m-I-α-MT) failed to produce hyperactivity in mice pretreated with a monoamine oxidase (MAO) inhibitor. In contrast, the amine releasers d,l-α-methyl-m-tyrosine and tetrabenazine caused pronunced stimulation in MAO-inhibited mice. These results are consistent with the view that norepinephrine depletion produced by α-MT and m-I-α-MT is the result of inhibition of biosynthesis and not of a release mechanism.

5-cyano-1-[3-(N-methylpyrrolidin-2R-ylmethyl)indol-5-yl] benzimidazole (CP-161,242): A potent, centrally active 5-HT1D receptor agonist and benzodiazepine partial agonist

Abstract The discovery of CP-161,242 (5-cyano-1-[3-(N-methylpyrrolidin-2R-ylmethyl)indol-5-yl]benzimidazole), a potent, selective, orally active central serotonin (5-HT1D) agonist [IC50 (binding) = 1.3 nM, EC50 (inhibition of adenylate cyclase) = 42 pM] and benzodiazepine ligand [IC50 (binding) = 3.3 nM], is presented.

Chapter 22. Drugs and Deterrence of Alcohol Consumption

Publisher Summary This chapter focuses on studies of drug therapy for deterring alcohol intake in the chronic alcoholic. First advocated as a therapeutic aid in alcoholism in 1948, disulfiram continues to occupy a role as an adjunct to psycnotherapy and behavior therapy. It is generally accepted that disulfiram acts by blocking aldehyde dehydrogenase, causing a toxic elevation of circulating acetaldehyde when alcohol is consumed. The antidiabetic sulfonylureas, for example, chlorpropamide and tolbutamide, comprise another structural class which interacts with alcohol to produce a mild disulfiram-like reaction. Accumulation of acetaldehyde has been observed after tolbutamide and alcohol in man, and after chlorpropamide and alcohol in rats. Both sulfonylureas enhance the vasodepressor responses of exogenous acetaldehyde in cats, supporting the inference of decreased metabolism of acetaldehyde. These experiments suggest inhibition of hepatic aldehyde dehydrogenase, however, only weak in vitro inhibition was found. Deterring capabilities of metronidazole, butyraldoxime, and some other drugs for alcohol consumption were also analyzed in some studies.