Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at 1 and 2/3 Subtypes

Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 09/2009; 332(1):4-16. DOI: 10.1124/jpet.109.158303
Source: PubMed


Abuse-liability-related effects of subtype-selective GABA(A) 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 alpha(1)-, alpha(2)-, alpha(3)-, and alpha(5)-containing GABA(A) 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 alpha(2) and alpha(3) and none at alpha(1) and alpha(5) 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 [(11)C]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 alpha(1) subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced alpha(2/3) subtype efficacy.

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    • "All had experience with one (PY) to five (YO) such studies of novel GABA-A allosteric modulators (Ator et al., 2010). Two baboons (GD, PY) had also served in an intravenous self-administration procedure in which they had experience with cocaine and five or six sedative/ anxiolytic compounds (Ator et al., 2010), and PY had experience with oral ethanol self-administration. Otherwise, GD, SHA, and YO had experience with bolus i.g. "
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    • "Drug history, including the type of drug used for self-administration training, has been shown to be a major determinant of the reinforcing effects of benzodiazepines (Nelson et al, 1983; Bergman and Johanson, 1985; Falk and Tang, 1989). Therefore, we examined self-administration of the different a1-sparing compounds described above in monkeys trained to self-administer either a benzodiazepine agonist (midazolam), or the psychomotor stimulant cocaine, in order to match the training conditions of Ator et al (2010). For comparisons across the two baseline conditions, we also included tests with non-selective benzodiazepine full agonists (midazolam, lorazepam) and a non-selective benzodiazepine partial agonist (MRK-696, see Table 1; Figure 1). "
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    • "It is important for future research to investigate whether anxiolytic cross-tolerance to the effect of TPA023 (or other subtype selective compound) is demonstrable in rodents chronically exposed to diazepam. If GABAA-α2/α3 subtype selective drugs do not induce tolerance in man, such subtype selective compounds might not engender clinical dependence [12], [61] or potentially drug abuse [62], [63]. This would constitute a significant clinical improvement over classical benzodiazepines in addition to GABAA-α2/α3 selective compounds' reduced propensity to engender sedation and postural instability [64]. "
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