title: Anticonvulsant effects of structurally diverse GABA(B) positive allosteric modulators in the DBA/2J audiogenic seizure test: Comparison to baclofen and utility as a pharmacodynamic screening model.
abstract: The GABA(B) receptor has been indicated as a promising target for multiple CNS-related disorders. Baclofen, a prototypical orthosteric agonist, is used clinically for the treatment of spastic movement disorders, but is associated with unwanted side-effects, such as sedation and motor impairment. Positive allosteric modulators (PAM), which bind to a topographically-distinct site apart from the orthosteric binding pocket, may provide an improved side-effect profile while maintaining baclofen-like efficacy. GABA, the major inhibitory neurotransmitter in the CNS, plays an important role in the etiology and treatment of seizure disorders. Baclofen is known to produce anticonvulsant effects in the DBA/2J mouse audiogenic seizure test (AGS), suggesting it may be a suitable assay for assessing pharmacodynamic effects. Little is known about the effects of GABA(B) PAMs, however. The studies presented here sought to investigate the AGS test as a pharmacodynamic (PD) screening model for GABA(B) PAMs by comparing the profile of structurally diverse PAMs to baclofen. GS39783, rac-BHFF, CMPPE, A-1295120 (N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide), and A-1474713 (N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide) all produced robust, dose-dependent anticonvulsant effects; a similar profile was observed with baclofen. Pre-treatment with the GABA(B) antagonist SCH50911 completely blocked the anticonvulsant effects of baclofen and CMPPE in the AGS test, indicating such effects are likely mediated by the GABA(B) receptor. In addition to the standard anticonvulsant endpoint of the AGS test, video tracking software was employed to assess potential drug-induced motor side-effects during the acclimation period of the test. This analysis was sensitive to detecting drug-induced changes in total distance traveled, which was used to establish a therapeutic index (TI = hypoactivity/anticonvulsant effects). Calculated TIs for A-1295120, CMPPE, rac-BHFF, GS39783, and A-1474713 were 5.31x, 5.00x, 4.74x, 3.41x, and 1.83x, respectively, whereas baclofen was <1. The results presented here suggest the DBA/2J mouse AGS test is a potentially useful screening model for detecting PD effects of GABA(B) PAMs and can provide an initial read-out on target-related motor side-effects. Furthermore, an improved TI was observed for PAMs compared to baclofen, indicating the PAM approach may be a viable therapeutic alternative to baclofen.
authors.affiliation: Neuroscience Discovery, AbbVie, Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: jordan.brown@abbvie.com.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Brown
authors.affiliation: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse, Ludwigshafen 67061, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Moeller
authors.affiliation: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse, Ludwigshafen 67061, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse, Ludwigshafen 67061, Germany.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Turner
authors.affiliation: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse, Ludwigshafen 67061, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Nimmrich
authors.affiliation: Drug Metabolism and Pharmacokinetics, AbbVie, Inc., North Chicago, IL 60064, United States.
authors.forename: Junli
authors.initials: J
authors.lastname: Ma
authors.affiliation: Neuroscience Discovery, AbbVie, Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Rueter
authors.affiliation: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse, Ludwigshafen 67061, Germany.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: van der Kam
authors.affiliation: Neuroscience Discovery, AbbVie, Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000737:chemistry* / Q000627:therapeutic use*; D001418:Baclofen / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000494:pharmacology; D004347:Drug Interactions; D018755:GABA Agonists / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D013460:Sulfur Isotopes / Q000493:pharmacokinetics
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; C569993:2-(1-(2-(4-chlorophenyl)-5-methylpyrazolo(1,5-a)pyrimidin-7-yl)-2-piperidinyl)ethanol; D000927:Anticonvulsants; D003517:Cyclopentanes; D018755:GABA Agonists; D009025:Morpholines; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D011720:Pyrazoles; D011743:Pyrimidines; D013460:Sulfur Isotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001418:Baclofen
keywords: Anticonvulsant; Audiogenic seizure; Baclofen; DBA/2J; GABA(B); Positive allosteric modulator