GABAa subtypeselective benzodiazepine site ligands

No NCEs have yet been reported with a high degree of selective affinity for GABAA receptor subtypes believed to be important for anxiolysis. However, compounds have been identified that, despite having similar affinities, show a degree of functional selectivity for different a-subunit-containing GABAA receptors (i.e., they behave as full or partial modulators of certain subtypes and neutral modulators of others). A compound preferentially potentiating a2-subunit-containing GABAA receptor responses could provide anxiolytic effects with a separation from sedation and memory impairment. A pyridine-2-one derivative, which behaves as a negative allosteric modulator with functional selectivity for a3-subunit-containing GABAA receptors, increased anxiety responses in rodents82'118 suggesting that potentiation of a3-subunit-containing GABAA receptor responses may also provide anxiolysis.

The triazalopyradizine, L-838417 (Figure 10b), had high affinity for a1-, a2-, a3-, and a5-subunit-containing GABAA receptors, but failed to affect GABA responses mediated by a1-subunit-containing GABAA receptors, and was a high affinity positive allosteric modulator at the remaining subtypes.106 In rodents, this compound had anxiolytic effects comparable to chlordiazepoxide in the EPM and fear-potentiated startle assays with little evidence for sedation. Anxiolytic activity was also observed in primates without sedation, with a low propensity for self-administration that might suggest lower abuse potential. 119 Additional compounds with functional selectivity for a2/3- or a3-subunit-containing GABAA receptors have been described118,120 with one reaching phase II clinical trials for GAD, but was discontinued.111

The pyridoindole derivative, SL-651498 (Figure 10b), had full efficacy as a positive allosteric modulator at a2- and a3-subunit-containing GABAA receptors, and was a partial agonist at a1- and a5-subunit-containing GABAA receptors. The compound has anxiolytic efficacy in a variety of tests, with higher doses required for sedative and ataxic effects.61 It reached phase II clinical trials, but no outcome or further studies have been reported.

The cyclopyrrolone, pagoclone (Figure 10b), had low nanomolar affinity for a1-, a2-, a3-, and a5-subunit-containing GABAA receptors and was a full agonist at GABAA-receptor-containing a3 subunits, with partial agonist activity at those containing a1, a2, and a5 subunits.82 In animals, pagoclone was anxiolytic with a lower propensity for sedative and muscle relaxant effects. Initial trials showed the pagoclone was effective in panic attack and GAD patients without sedative effects. Additional studies failed to replicate these initial findings.

Other compounds with some degree of functional selectivity towards a2- and/or a3-subunit-containing GABAA receptors and anxiolytic effects include: the quinolone 'compound 4,'121 NGD 91-3, and ELB-13982,122; few details are available on these compounds.

There is clear evidence from clinical studies that positive allosteric modulators with partial efficacy (bretazenil, ocinaplon) are anxiolytic with efficacy comparable to standard BZs, but why bretazenil produces sedation at anxio-lytic doses, whereas this appears not to be the case with ocinaplon is difficult to reconcile with the receptor profiles of these compounds. Clinical studies with compounds showing functional selectivity for a2- and a3-subunit-containing GABAA receptors have been inconclusive (pagoclone) and further studies are clearly needed to validate the potential benefit of this profile. It may also be that the GABAA receptor subtype story is more complicated. Evidence exists that a substantial proportion of individual native GABAA receptors contain two different a subunits, e.g., a1a2bg a1a3bg.123 The cellular location and functional role of these 'mixed a subunit' GABAA receptor subtypes, as well as their functional response to BZ site ligands remains to be seen, but may explain some of the anomalies observed to date.

Conquering Fear In The 21th Century

Conquering Fear In The 21th Century

The Ultimate Guide To Overcoming Fear And Getting Breakthroughs. Fear is without doubt among the strongest and most influential emotional responses we have, and it may act as both a protective and destructive force depending upon the situation.

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