Anticonvulsant receptor models

The anxiolytic properties of 5-HT3 receptor antagonists have been demonstrated in several animal models of anxiety. In these models, the 5-HT3 antagonists mimic the anxiolytic effects of the benzodiazepines but differ from the latter in their lack of sedative, muscle relaxant and anticonvulsant action. These compounds appear to be extremely potent... 

Post RM, Ketter TA, Pazzaglia PJ, et al. Receptor, ion channel, and neuropeptide targets for drug development implications from the anticonvulsant model. Am Coll Neuropsychopharmacol Abstr Panels Posters 1992 Dec 9. 

Recently, the therapeutic potential of stem cells engineered to release adenosine as a local source to augment endogenous adenosinergic functions was assayed in two cell transplantation experiments (Li et al. 2007, 2008 Boison 2008). Most of the studies about the role of adenosine as an anticonvulsant emphasize the preeminent involvement of A1 adenosine receptors. However, several studies using different experimental models of epilepsy have investigated the role of adenosine A2a and A3 receptors in this condition. 

Colburn WA (1981) Simultaneous pharmacokinetic and pharmacodynamic modeling. J Pharmacokin Biopharm 9 367 Dingemanse J, Van Bree JB, Danhof M (1989) Pharmacokinetic modeling of anticonvulsant reponse of Phenobarbital in rats. J Pharmacol Exp Ther 249 601-608 Hoffman A, Goldberg A (1994) The relationship between receptor-effector unit heterogeneity and the shape of the concentration-effect profile pharmacodynamic implications. J Pharmacokinet Biopharm 22 449-468... 

Unfortunately, the impact of anticonvulsants on NA-induced seizures has not been modeled in this way. Given many countermeasures have different ligand-receptor interactions, such an approach would need to be expanded to the other excitatory and inhibitory neurotransmitters and... 

Adenosine, which may be an endogenous anticonvulsant, continues tn serve as a model but, for reasons such as poor brain distribution and an array of cardiovascular effects of agonists, has not yet yielded useful drugs. Elaboration of roles of receptor subtypes may give leads for drug design. 

MandemaJW, SansomLN, Dios-VieitezMC, etal. Pharmacokinetic-pharmacodynamic modeling of the electroencephalographic effects of benzodiazepines. Correlation with receptor binding and anticonvulsant activity. / Pharmacol Exp Ther. 1991 257(l) 472-478. 

CGP 35348 is a phosphinic acid derivative, a (GABAb) GABA receptor ANTAGONIST. It is used as a pharmacological tool, and shows ANTICONVULSANT / ANTIEPILEPTIC properties in animal models. 

The quadracyclic ( )-5-aminocarbonyl-10,ll-dihydro-5H-dibenzo[a,c ]cyclohepten-5,10-imine (ADCI,47), results from the fusion of two active anticonvulsant compounds, MK 801 (dizocilpine,46), a potent noncompetitive NMDA antagonist (224, 225) and carbamazepine (2). The compound acts as a selective, low affinity channel blocker of the NMDA receptor and also possesses Na" channel-blocking activity (226). ADCI is devoid of the tendency to cause behavioral impairment as MK 801. ADCI is a racemate, although the (- -)-enantiomer displays a four- to fivefold greater potency at the NMDA receptor and a greater than twofold potency for seizure models in animals. There was no enantioselectivity in the Na" channel evaluation, however. The (- -)-enantiomer (SGB-017)is currently in Phase II of clinical development. 

Several authors have provided insight into the putative MBS receptor based on their structure-activity data. As noted by Unverferth et al. (281), there have been several attempts to postulate a general pharmacophore for the different anticonvulsant classes, all of which are anti-MES in animal studies and are, or have the potential to be, effective in generalized tonic-clonic seizures. These include benzodiazepines (282) barbiturates (283) triazolines (284) semicarbazones (248-261) and enami-nones (286-288), respectively and for different compounds with similar anticonvulsant profiles (289-292). The Unverferth model (Fig. 6.11) provides an excellent representation of the current anticonvulsants phenytoin (1), carbamazepine (2), lamotrigine (11), zonisamide (13), and rufinamide (60). Remace-mide (58) is also included as a possible candidate (Fig. 6.12). 

A confusing picture emerges when cannabinoids are evaluated in animal models of epilepsy (Karler and Turkanis 1981 Consroe and Snider 1986). CBD has anticonvulsant properties with a spectrum distinct from standard anticonvulsants, apparently not hampered by the development of tolerance but with a varying profile according to the species tested. THC can produce seizures in some circumstances but is anticonvulsant in others. In a recent study, THC (10 mg/kg) completely abolished spontaneous seizures in the rat pilocarpine model of epilepsy (Wallace et al. 2003). The results also indicated that endogenous cannabinoid tone may modulate seizure termination and duration via the CBi receptor. 

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