Synthetic cannabinoids, potential therapeutic agents of the central nervous system

Synthetic cannabinoids, potential therapeutic agents of the central nervous system

S184 S.20 Cannabinoids in health and disease catalepsy, and hypothermia, are used to infer camtabinoid activity (Little et al., 1988). Naturally occ...

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S.20 Cannabinoids in health and disease

catalepsy, and hypothermia, are used to infer camtabinoid activity (Little et al., 1988). Naturally occurring and synthetic camtabinoids reliably elicit each of these responses. A strong positive correlation between binding potency and in viva potency in the tetrad of behavioral tests has been found (Compton et al., 1993). Of importance, SR 141716A antagonizes these effects in most active cannabinoids tested. In addition to investigating the effects of cannabinoids following acute administration, the mouse tetrad test can be used to evaluate the consequences of repeated drug administration. A profound tolerance develops to each of the four pharmacological effects following repeated administration of A9THC, CP 55,940, or WIN 55,212-2 in mice (Fan et al., 1994). The high prevalence of humans using camrabinoids for recreational or medicinal reasons suggests that the occurrence of physical withdrawal could become an issue when the drug is discontinued. Previously, it had been difficult to establish a reliable animal model of cannabinoid dependence relying on methodologies that used abrupt withdrawal. With the availability of SR 141716A, however, this antagonist precipitates reliable speciesspecific withdrawal syndromes in A9-THC tolerant mice, rats, and dogs (Aceto et al., 1996). The heterogeneous distribution of cannabinoid receptors in the central nervous system suggests that the different behavioral effects of the cannabinoids may be mediated by distinct neuroanatomical substrates. One strategy to elucidate the neural substrates of cannabinoid activity is to assess the behavior in rats following microinjection of a potent cannabinoid, such as CP 55,940, into specific brain sites that are associated with cannabinoid-sensitive behaviors and also contain high concentrations of cannabinoid receptors (Lichtman et al., 1996). Infusion of CP 55,940 into the periaqueductal gray (PAG), a brain area strongly implicated in antinociception, elicited antinociceptive, cataleptic, and hypothermic effects. The antinociceptive effects were dose-dependent and exhibited regional specificity, as they only occurred when the drug was administered into the posterior ventrolateral PAG, not in the dorsolateral aspect, anterior ventrolateral region, or outside of the PAG. In contrast, infusion of CP 55,940 into the caudate putamen, a brain area associated with movement, produced catalepsy, but failed to produce either antinociception or hypothermia, suggesting that stimulation of cannabinoid receptors in this area are relatively selective for catalepsy. Finally, microinjection of CP 55,940 into the hippocampus, a brain area associated with learning and memory, impaired working memory in a dose-dependent manner, as assessed in a radial arm maze task. The effects of intrahippocampal CP 55,940 were relatively specific to cognition because no other cannabinoid pharmacological effects (i.e., locomotor depression, antinociception, hypothermia, or catalepsy) were detected. In conclusion, the use of behavioral models to evaluate cannabinoids has increased our understanding of the pharmacology of this class of drugs. Specifically, the various models have been used to characterize the effects of cannabinoids on nociception, memory, motor behavior, as well as many other processes. In combination with the cannabinoid antagonist SR 141716A, these tests have can help elucidate whether a drug has cannabinoid activity and is acting through a CBi receptor mechanism of action. Behavioral models have also been developed to investigate tolerance and dependence following repeated drug exposure. Finally, the existence of cannabinoid receptors and endogenous ligands that bind to these receptors suggest the possibility that an endogenous camtabinoid system plays a physiological role in behavior. On going and future work will undoubtedly elucidate the function of the endogenous camtabinoid system.

References [I] Aceto, M., States, S., Lowe, .I., Martin, B., 1996. J. Pharmacol. Exp. Ther. 278, 1290-1295. [2] Compton, D.R., Rice, K.C., De Costa, B.R., Razdan, R.K., Melvin, L.S., Johnson, M.R., Martin, B.R., 1993. J. Pharmacol. Exp. Ther. 265, 218-226. [3] Fan, E, Compton, D.R., Ward, S., Melvin, L., Martin, B.R., 1994. J. Pharmacol. Exp. Ther. 271, 1383-1390. [4] Lichtman, A.H., Cook, S.A., Martin, B.R., 1996. J. Pharmacol. Exp. Ther. 276, 585-593. [5] Little, PJ., Compton, D.R., Johnson, M.R., Melvin, L.S., Martin, B.R., 1988. J. Pharmacol. Exp. Ther. 247, 104&1051.


Synthetic cannabinoids, potential therapeutic agents of the central nervous system

E. Pop. Alchem Laboratories Corpomtion, 13305 Rachael Boulevard, Alachua, FL 3261.5, USA Although natural cannabinoids, including Ag-tetrahydrocamrabinol (THC) possess numerous beneficial effects, their use in medical purposes is limited due to their psychotropic activity. Recent developments, which include identification of cannabinoid receptors (CBl and CB2) and their endogenous ligands, led to a better understanding of mechanisms of action of these compounds. As a result, important steps toward the therapeutic use of cannabinoids, endocannabmoids and their synthetic analogs have been made. THC and its psychoactive natural 6aR-tram analogs, cannabidiol, a natural nonpsychotropic compound and several synthetic camiabimimetics including WIN-55212-2 and CP-55940 are protective against excitatory amino acid neurotoxicity. While the use of most of these compounds is not recommended due to unwanted side-effects, cannabinol, well tolerated by humans is currently developed for the treatment of ischemic stroke. Dexanabinol (HU-21 l), a synthetic cannabinoid belonging to the 6aStrans optical series has no affinity to cannabinoid receptors and is nonpsychotropic (Mechoulam et al., 1990). other properties, including NMDA receptor antagonist, radical scavenger and tumor necrosis factor (TNFa) suppressor, prompted development of dexanabinol as a neuroprotective agent. Animal trauma model studies demonstrated that dexanabinol has significant protective action at relatively low doses. The extent of brain damage and neuroprotective effect evaluated by standard parameters indicated that a single injection of dexanabinol provided long-term protection and enhanced functional recovery of the nervous system. Stroke/cardiac arrest model studies showed that dexanabinol confered signiticant protection against both neurobehavioral and histopathological effects of transient global forebrain ischemia. Phase I clinical studies designed to assess the safety of the product in humans were performed on 30 people treated iv with escalating doses (4 to 48 mg/vohmteer) of dexanabinol. Subjective well being, hematological tests, urinalysis, ECG recordings and intraocular pressure measurements indicated no serious adverse events in the treated subjects (Brewster et al., 1997). Phase II escalating-dose (48, 150 and 200 mg) clinical experiments were performed with the objective to evaluate the safety of dexanabinol in patients with traumatic brain injury. Multi center, randomized, double masked study of single dose of dexanabinol iv solution with vehicle placebo control was performed on 101 patients (52 received drug and 49 placebo). Clinical endpoints indicated good safety profile of the drug in the treated patients. Intracranial pressure above a threshold of 25 mm Hg, an important risk factor and predictor of a poor neurological outcome, was significantly reduced (40-70%). Neurological outcomes in


,921 Social anxiety and PTSD: from stress to avoidance the study established a trend of efficacy, a higher percentage of the treated patients achieving Good Neurological Outcome. Optimal dose of drug, selected based on these experiments will be employed in a pivotal international trial on several hundred patients scheduled to commence soon. Other potential uses of dexanabinol include treatment of Parkinson’s, Alzheimer’s disease and multiple sclerosis. The Sanofi-Synthelabo compound SR141716, a non-classical diarylpyrazole type derivative is the tirst selective CBl receptor ligand (Rinaldi-Carmona et al., 1994). Binding studies indicated that SR-1417 16 has nanomolar afhnity to the CBl receptor and only negligible activity at the CB2 site. In vitro, SR-141716 antagonizes the inhibitory effects of the cannabinoid receptor agonists while in vivo antagonizes classical pharmacological and behavioral effects of CBl agonists. SR141716 might function as a reverse agonist at the CBl receptor. As a selective, orally active CBl antagonist, SR-141716 has been used in a large number of studies targeting the involvement of CBl in the cannabimimetic activity of various synthetic and endocannabinoids, and opened new possibilities for identification and characterization of cannabinoid-dependent neuroregulations. Administered alone, SR-14 17 16A altered several physiological or behavioral parameters, such as arousal, memory consolidation, sucrose intake, incentive learning and nociception, indicating that endogenous cannabinoid systems may be tonically active in certain conditions; it might be possible that endogenous cannabinoid systems are implicated in neuronal dysregulation leading to pathological conditions. It was suggested that some schizophrenic symptoms such as perceptual disturbance may be related to a deregulation of the endogenous cannabinoid systems. Clinical reports indicated the occurrence of psychodysleptic effects, included distorted sensory perceptions, impaired judgement and dissociation of ideas following administration of cannabis. These reports and observation that cannabinoid agonists activate dopaminergic systems, determined examination of effects of SR141716A on neuronal functioning as compared to antipsychotic drugs. Typical and atypical neuroleptic agents increase the expression of immediate early genes in various brain regions, the effects being sensitive to dopamine Dz-like receptor stimulation. It was demonstrated that SR- 141716 had similar effects, probably resulted from blockade of endogenous cannabinoid tone on CBl receptors. The results suggested that blockade of CBl receptors could have beneficial effects on pathology of schizophrenia. SR-141716A is currently developed as a CNS agent for the potential treatment of schizophrenia and psychosis. A phase II “meta-trial” comparing the relative efficacy of four schizophrenia investigational candidates has been performed. The trial included 420 patients, with 63 receiving each of the four compounds and two groups of 84 patients receiving either placebo or haloperidol. The outcome of the study is not known (Kendal, 2000). L-DOPA is the classical therapeutic treatment for Parkinson’s disease. However, long-term therapy results in several side-effects, including induced dyskinesia. It was reported that co-administration of SR1417 16A with L-DOPA in animal models, reduced dyskinesia without affecting the antiparkinsonia.n efficacy of L-DOPA. This effect is of interest and is further evahtated. The potential pharmaceutical value of endogenous ligands to cannabinoid receptors, anandamide and 2-AG is also investigated. Of particular interest is the interaction of anandamide and several neuroreceptor systems which includes: enhancement of GABAergic neurotransmission, inhibition of motor behavior paralleled by lowering the activity of nigrostriatal dopaminergic neurons, inhibition of the presynaptic glutamate release, and inhibition of

exocytic noradrenaline release. These actions and the possible, currently evaluated role of endooamrabinoids in schizophrenia might have therapeutic potential. It is expected that the intensive work in the area of cannabinoids will result in important discoveries with valuable therapeutic applications (Pop, 1999).

[1] Brewster, M. E., Pop, E., Foltz, R. L., Reuschel, S., Griffith, W., Amselem, S., and Biegon, A. (1997). Clinical pharmacokinetics of escalating iv doses of dexanabinol (HU-2 1 l), a neuroprotectant agent, in normal volunteers, Int. J. Clin. Pharmacol. 35, 361-365. [2] Kendall, D. (2000) SR-141716A Sanofi-Synthelabo, Current Opinion CPNS Investigational Drugs 2, 112-122. [3] Mechoulam, R., Lander, N., Breuer, A. and Zahaika, J. (1990) Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative, Tetrahedron: Asymmetry 1, 3 15-3 19. [4] Pop, E. (1999) Developing camrabinoids as potential central nervous system agents, Current Opinion CPNS Insvestigational Drugs 1, 587596. [5] Rinaldi-Carmona, M., Barth, F., Heaulme, M., Shire, D., Calandra, B., Congy, C., Martinez, S., Maruani, J., nehat, G., Caput, D., Ferrara, E, Soubrie, P., Breliere, J.C. and Le Fur, G. (1994) SR-141716A, a potent and selective antagonist of the brain camrabinoid receptor, FBBS Lett. 350,240-244.

S.21 Social anxiety and PTSD: from stress to avoidance 15.21.011The epidemiology, natural history, and pharmacoeconomlcs, PTSD

of Social Anxiety and

R.C. Kessler. Department of Health Care Policy, Harvard Medical School, 180 Longwood Avenue, Boston, 444 02115, USA Purpose: To review the literature on the prevalence, course, and societal costs of Social Anxiety Disorder (Social Phobia) and PostTraumatic Stress Disorder (PTSD) Method: A literature search of computerized databases for published reports on anxiety, social phobia, trauma, and PTSD Results: Prevalence: Epidemiologic surveys suggest that Social Anxiety Disorder and PTSD both commonly occur in the general population. The estimated prevalence of Social Anxiety Disorder in general population surveys is as high as 16% lifetime and 8% in a year. The generalized subtype of Social Anxiety Disorder - a subtype found in approximately 50% of lifetime cases and in up to two-thirds of cases in a year - is much more severe and impairing than other cases. As the name implies, strong fear and avoidance of a wide range of social interaction and performance situations characterize this generalized subtype. Evidence from synthetic cohort studies indicates that the prevalence of generalized Social Anxiety Disorder has increased over the past several decades in the United States. Trends in other countries have not been reported. The estimated prevalence of PTSD in general population surveys in western societies is as high as 15% lifetime and 6% in a year. These prevalences vary greatly across countries depending on variation in trauma exposure. Although representative epidemiologic studies have not been carried out in countries experiencing prolonged political or ethnic violence, studies of refugees from such countries early show a substantially higher conditional risk of PTSD among people exposed to these types of ongoing horrific trauma than among victims of the traumas more characteristic of developed countries. For example, 65% of a sample of Bosnian refugees resettled in the U.S. were found to suffer from PTSD.