Synthesis of Subtype Selective Bz/GABAA Receptor Ligands for the Treatment of Anxiety, Epilepsy and Neuropathic Pain, as Well as Schizophrenia and Asthma
The α2/α3 subtype selective Bz/GABAA receptor positive allosteric modulator HZ-166 (3) has been shown to be a nonsedating anxiolytic with anticonvulsant and antihyperalgesic activity. However, instability in vitro and in vivo has hindered its advancement into clinical trials. A series of ligands based off HZ-166 (3) were synthesized. Many of these ligands were designed to increase metabolic stability, while others were synthesized to study the effects that electronics and sterics have on the efficacy exerted when bound to the GABAA receptor. The α3 subtype selective methyl ester MP-III-024 (19) was shown to have increased resistance to metabolism in in vitro liver microsomal studies and exhibited significant anxiolytic and antihyperalgesic effects in mice without showing signs of sedation. However, pharmacokinetic studies indicated that esters as a functional group may not be suitable for extensive preclinical studies.
A series of heterocyclic bioisosteres were synthesized to specifically overcome short half-lives in vivo. The oxadiazole MP-III-080 (34) and oxazole KRM-II-81 (36) underwent pharmacokinetic studies and were both found to exist in plasma and brain samples in high levels. These results indicated that these and related heterocycles would be stable in vivo to undergo extensive preclinical trials. A dozen ligands were assessed in vivo in an anxiolytic marble burying assay and a rotarod assay designed to measure ataxic effects. The results from these studies and other in vitro protocols led to additional studies using KRM-II-81 (36). This oxazole 36 was found to exhibit significant anxiolytic and anticonvulsant properties, including reducing network firing rate frequency in human brain tissue from a patient suffering from resistance epilepsy. In addition, KRM-II-81 (36) was found to be more efficacious than gabapentin to reverse the effects of hyperalgesia in a neuropathic pain model at a lower dose using rats, as well as exhibiting antidepressant-like effects.
The α5 GABAA receptor subtype has been linked to the cognitive disorders in such diseases as schizophrenia, bipolar I disorder and major depressive disorder. The enantiomers SH-053-2\u27F-S-CH3 (51) and SH-053-2\u27F-R-CH3 (52) have been shown to be α2/α3/α5- and α5- subtype selective agonists, respectively. Both ligands (S)-51 and (R)-52 have been shown to reduce some positive symptoms of schizophrenia; the S-enantiomer 51 was active in the poly(I:C) model of schizophrenia while the R-enantiomer 52 was active in the MAM-model of schizophrenia. Due to the high rate of comorbidity of schizophrenia with anxiety, epilepsy and depression, the S-enatiomer (51) is shown here to be useful in these instances exhibiting anxiolytic and anticonvulsant properties. In addition, work on analogs of 52 produced MP-III-004 (63), an α5 subtype selective ligand with reduced efficacy at the α1, α2 and α3 subtypes as compared to 52, as well as the very potent α5 positive allosteric modulator MP-III-022 (65). This methyl amide 65 was shown to activate α5 subtypes in vivo in rats at low concentrations, providing a valuable tool to study the α5 GABAA receptor subtype. Recent work has shown SH-053-2\u27F-R-CH3 (52) and MP-III-022 (65) exert antidepressant-like effects in mice, indicating a new use for α5 subtype selective ligands. Moreover, work by Emala et al. has discovered a use for α5 subtype selective ligands outside of the central nervous system. A number of the ligands, especially the α5 selective acid 73, presented herein have been shown to relax precontracted human and guinea pig airway smooth muscle and may provide a novel treatment for those who suffer from asthma