Developing New 4-PIOL and 4-PHP Analogues for Photoinactivation of γ-Aminobutyric Acid Type A Receptors.

The critical roles played by GABAA receptors as inhibitory regulators of excitation in the central nervous system has been known for many years. Aberrant GABAA receptor function and trafficking deficits have also been associated with several diseases including anxiety, depression, epilepsy, and insomnia. As a consequence, important drug groups such as the benzodiazepines, barbiturates, and many general anesthetics have become established as modulators of GABAA receptor activity. Nevertheless, there is much we do not understand about the roles and mechanisms of GABAA receptors at neural network and systems levels. It is therefore crucial to develop novel technologies and especially chemical entities that can interrogate GABAA receptor function in the nervous system. Here, we describe the chemistry and characterization of a novel set of 4-PIOL and 4-PHP analogues synthesized with the aim of developing a toolkit of drugs that can photoinactivate GABAA receptors. Most of these new analogues show higher affinities/potencies compared with the respective lead compounds. This is indicative of cavernous areas being present near their binding sites that can be potentially associated with novel receptor interactions. The 4-PHP azide-analogue, 2d, possesses particularly impressive nanomolar affinity/potency and is an effective UV-inducible photoinhibitor of GABAA receptors with considerable potential for photocontrol of GABAA receptor function in situ.