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

Abstract

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 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 photo-inactivate GABAA receptors.Most of these new analogues show higher affinities/potencies compared to 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 photo-inhibitor of GABAA receptors with considerable potential for photo-control of GABAA receptor function in situ.

Identification of potent anti-fibrinolytic compounds against plasminogen and tissue-type plasminogen activator using computational approaches

“…Based on the findings of these studies, the ideal novel oral fibrinolysis inhibitor is expected to work on a mechanism of action similar to that of TXA, having suitable dosing and higher selectivity over GABAa. Of late, some new encouraging drugs have been discovered like 4-PIOL and PS-112 (TXA-derived active site inhibitors) but, to date, their detailed profiling and testing have not been performed (Mortensen et al, 2019; Law et al, 2017). Even though considerable research has been undertaken, clinically safe fibrinolysis inhibitors have not reached the market.…”