Pharmacological Properties of DOV 315,090, an ocinaplon metabolite.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Berezhnoy
Dmytro
D
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA.
Gravielle
Maria C
MC
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA.
Downing
Scott
S
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA.
Kostakis
Emmanuel
E
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA.
Basile
Anthony S
AS
DOV Pharmaceutical, Inc, 150 Pierce St., Somerset, NJ 08873-4185, USA.
Skolnick
Phil
P
DOV Pharmaceutical, Inc, 150 Pierce St., Somerset, NJ 08873-4185, USA.
Gibbs
Terrell T
TT
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA.
Farb
David H
DH
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA.
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000378:metabolism / Q000494:pharmacology*; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D014982:Xenopus laevis
D014151:Anti-Anxiety Agents; D003497:Cyclic N-Oxides; C534459:DOV 315090; D011743:Pyrimidines; D011963:Receptors, GABA-A; C501948:ocinaplon; D003975:Diazepam