The effects of the nonselective benzodiazepine lorazepam and the α₂/α₃ subunit‐selective GABA_A receptor modulators AZD7325 and AZD6280 on plasma prolactin levels

Abstract

Compounds with selectivity for GABAA receptor subtypes may differ significantly from nonselective benzodiazepines in their dopaminergic effects in vivo. To explore the exact role of the GABAA receptor subtypes in the regulation of prolactin secretion and the differential effects of selective and nonselective GABA receptor modulators, the effects of the nonselective benzodiazepine lorazepam, as well as two novel α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280, on prolactin levels were measured in healthy male volunteers. Following administration of lorazepam at 2 mg doses and AZD6280 at 10 mg and 40 mg doses, prolactin levels increased significantly compared with placebo (difference 42.0%, 19.8%, and 32.8%, respectively), suggesting that the α2 and/or α3 receptor subtypes are involved in GABAergic modulation of prolactin secretion, although possible roles of the α1 and α5 receptor subtypes are not excluded. The increases in prolactin levels after administration of AZD7325 at 2 mg and 10 mg doses (difference 7.6% and 10.5%, respectively) did not reach statistical significance, suggesting that doses of AZD7325 or intrinsic efficacy at the α2 and α3 receptor subtypes may have been too low.

Hypnotics and Triazolobenzodiazepines - Best Predictors of High-Dose Benzodiazepine Use: Results from the Luxembourg National Health Insurance Registry

“…The α 1 GABA A receptors would be responsible for sedation and anterograde amnesia, while anxiolysis and muscle relaxation would be due to their benzodiazepine agonist effects on α 2 GABA A receptors [40] . The marked differences between anxiolytics and hypnotics regarding the risks for continuous and highdose use found in our study could be explained by their differences in ligand binding with high affinity to the α 1 -subtype GABA A receptors for hypnotics versus high affinities to α 2 -and α 3 -subtypes and low-affinity α 1 -subtype for anxiolytics [42] .…”

Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety

“…Potential peripheral neuroendocrine biomarkers for the effects of selective and nonselective GABA receptor modulators were also explored [121]. The effects of two novel α2 subunit-selective GABA (A) receptor modulators, AZD7325 and AZD6280, on serum prolactin levels were evaluated in healthy male volunteers and compared with those of the nonselective GABA(A) modulator lorazepam.…”

Cinnoline Scaffold—A Molecular Heart of Medicinal Chemistry?

“…AZD7325 ( 51 ) and AZD6280 ( 52 ) depicted in Figure 27 were identified as positive modulators at α2/α3 and negative modulators at α5 GABA A receptors and exhibited a potent anxiolytic-like effect without sedation or cognitive impairment [13,58]. These compounds have undergone clinical trial phase I [59,60]. Moreover, AZD7325 was studied in two phase II proof-of-concept trials in patients with general anxiety disorders (NCT 00807937 and NCT00808249) as well as in a phase II proof-of-mechanism in patients with autism spectrum disorders (NCT01966679).…”