Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α1 and α2/3 Subtypes

  1. Nancy A. Ator,
  2. John R. Atack1,
  3. Richard J. Hargreaves,
  4. H. Donald Burns and
  5. Gerard R. Dawson2
  1. Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (N.A.A.); Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, United Kingdom (J.R.A., G.R.D.); and Imaging Research and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania (R.J.H., H.D.B.)
  1. Address correspondence to:
    Dr. Nancy A. Ator,
    Behavioral Biology Research Center, 5510 Nathan Shock Dr., Ste. 3000, Johns Hopkins Bayview Campus, Baltimore, MD 21224-6823.
    E-mail: ator{at}jhmi.edu

  1. Portions of these data were presented: Ator NA (2002) Differential abuse liability profiles of GABA-A subtype selective compounds. Annual Meeting of the American College of Neuropsychopharmacology; 2002 Dec 7–11; San Juan, Puerto Rico. American College of Neuropsychopharmacology, Nashville, TN; and conclusions on self-administration were reviewed in Ator (2005).

Abstract

Abuse-liability-related effects of subtype-selective GABAA modulators were explored relative to the prototypic benzodiazepine lorazepam. 7-Cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (TPA123) has weak partial agonist efficacy at α1-, α2-, α3-, and α5-containing GABAA receptors, whereas 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) has weaker partial agonist efficacy at α2 and α3 and none at α1 and α5 subtypes. For both compounds, preclinical data suggested efficacy as nonsedating anxiolytics. Self-injection of TPA123 (0.0032–0.1 mg/kg) and TPA023 (0.0032–0.32 mg/kg) was compared with lorazepam (0.01–0.32 mg/kg) in baboons. TPA123 and lorazepam maintained self-injection higher than vehicle at two or more doses in each baboon; peak rate of self-injection of lorazepam was higher than TPA123. Self-injected lorazepam and TPA123 also increased rates of concurrently occurring food-maintained behavior. After the availability of self-administered TPA123 doses ended, an effect consistent with a mild benzodiazepine-like withdrawal syndrome occurred. In contrast with lorazepam and TPA123, TPA023 did not maintain self-administration. Positron emission tomography studies showed that TPA023 produced a dose-dependent inhibition in the binding of [11C]flumazenil to the benzodiazepine binding site in the baboon, which was essentially complete (i.e., 100% occupancy) at the highest TPA023 dose (0.32 mg/kg). In a physical dependence study, TPA023 (32 mg/kg/24 h) was delivered as a continuous intragastric drip. Neither flumazenil at 14 days nor stopping TPA023 after 30 to 31 days resulted in the marked withdrawal syndrome characteristic of benzodiazepines in baboons. In the context of other data, elimination of efficacy at the α1 subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced α2/3 subtype efficacy.

Footnotes

  • ↵1 Current affiliation: Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.

  • ↵2 Current affiliation: P1vital, Wokingham, Berkshire, United Kingdom.

  • This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA04133] (for the study of lorazepam and manuscript preparation by N.A.A.); Merck Research Laboratories (West Point, PA) for PET studies and blood plasma analyses; and Merck, Sharp & Dohme for behavioral studies with TPA123 and TPA023.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.158303

  • ABBREVIATIONS:

    L-838417
    7-(1,1-dimethylethyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,5-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine
    TPA123
    7-Cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine
    TPA023
    7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine
    PET
    positron emission tomography
    FR
    fixed ratio
    TAC
    time-activity curve
    SUV
    standard uptake value
    SB
    specific binding.

    • Received July 4, 2009.
    • Accepted September 28, 2009.
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  1. Published online before print September 29, 2009, doi: 10.1124/jpet.109.158303 JPET January 2010 vol. 332 no. 1 4-16
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