TY - JOUR

T1 - Developing New 4-PIOL and 4-PHP Analogues for Photoinactivation of γ-Aminobutyric Acid Type A Receptors

AU - Mortensen, Martin

AU - Krall, Jakob

AU - Kongstad, Kenneth T

AU - Brygger, Benjamin M

AU - Lenzi, Ombretta

AU - Francotte, Pierre

AU - Sørensen, Troels E

AU - Nielsen, Birgitte

AU - Jensen, Anders A

AU - Smart, Trevor G

AU - Frølund, Bente

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1021/acschemneuro.9b00478

DO - 10.1021/acschemneuro.9b00478

M3 - Journal article

C2 - 31589403

VL - 10

SP - 4669

EP - 4684

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 11

ER -