Berezhnoy Dmytro, Gravielle Maria C, Downing Scott, Kostakis Emmanuel, Basile Anthony S, Skolnick Phil, Gibbs Terrell T, Farb David H
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA.
DOV Pharmaceutical, Inc, 150 Pierce St., Somerset, NJ 08873-4185, USA.
BMC Pharmacol. 2008 Jun 13;8:11. doi: 10.1186/1471-2210-8-11.
Compounds targeting the benzodiazepine binding site of the GABAA-R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for pre-anesthetic sedation and muscle relaxation. It has been hypothesized that these various pharmacological effects are mediated by different GABAA-R subtypes. If this hypothesis is correct, then it may be possible to develop compounds targeting particular GABAA-R subtypes as, for example, selective anxiolytics with a diminished side effect profile. The pyrazolo[1,5-a]-pyrimidine ocinaplon is anxioselective in both preclinical studies and in patients with generalized anxiety disorder, but does not exhibit the selectivity between alpha1/alpha2-containing receptors for an anxioselective that is predicted by studies using transgenic mice.
We hypothesized that the pharmacological properties of ocinaplon in vivo might be influenced by an active biotransformation product with greater selectivity for the alpha2 subunit relative to alpha1. One hour after administration of ocinaplon, the plasma concentration of its primary biotransformation product, DOV 315,090, is 38% of the parent compound. The pharmacological properties of DOV 315,090 were assessed using radioligand binding studies and two-electrode voltage clamp electrophysiology. We report that DOV 315,090 possesses modulatory activity at GABAA-Rs, but that its selectivity profile is similar to that of ocinaplon.
These findings imply that DOV 315,090 could contribute to the action of ocinaplon in vivo, but that the anxioselective properties of ocinaplon cannot be readily explained by a subtype selective effect/action of DOV 315,090. Further inquiry is required to identify the extent to which different subtypes are involved in the anxiolytic and other pharmacological effects of GABAA-R modulators.
作用于GABAA受体苯二氮䓬结合位点的化合物被广泛用于治疗焦虑症、癫痫和失眠，以及用于麻醉前镇静和肌肉松弛。据推测，这些不同的药理作用是由不同的GABAA受体亚型介导的。如果这一假设正确，那么有可能开发出针对特定GABAA受体亚型的化合物，例如副作用较小的选择性抗焦虑药。吡唑并[1,5-a]嘧啶类药物奥西那普隆在临床前研究和广泛性焦虑症患者中均具有抗焦虑选择性，但在使用转基因小鼠的研究预测的含α1/α2受体的抗焦虑选择性方面未表现出选择性。
我们推测奥西那普隆在体内的药理特性可能受一种对α2亚基比对α1具有更高选择性的活性生物转化产物影响。给予奥西那普隆1小时后，其主要生物转化产物DOV 315,090的血浆浓度为母体化合物的38%。使用放射性配体结合研究和双电极电压钳电生理学评估了DOV 315,090的药理特性。我们报告称，DOV 315,090在GABAA受体上具有调节活性，但其选择性谱与奥西那普隆相似。
这些发现表明DOV 315,090可能有助于奥西那普隆在体内的作用，但奥西那普隆的抗焦虑选择性特性不能轻易地通过DOV 315,090的亚型选择性效应/作用来解释。需要进一步研究以确定不同亚型在GABAA受体调节剂的抗焦虑和其他药理作用中所涉及的程度。
