Azogabazine; a photochromic antagonist of the GABAA receptor.
The design and synthesis of azogabazine is described, which represents a highly potent (IC50 = 23 nM) photoswitchable antagonist of the GABAA receptor. An azologization strategy is adopted, in which a benzyl phenyl ether in a high affinity gabazine analogue is replaced by an azobenzene, with resultant retention of antagonist potency. We show that cycling from blue to UV light, switching between trans and cis isomeric forms, leads to photochemically controlled antagonism of the GABA ion channel.
Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. j.r.baker@ucl.ac.uk.
Rosemary
R
Huckvale
Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. t.smart@ucl.ac.uk.
Martin
M
Mortensen
Pfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridgeshire, CB21 6GS, UK.
David
D
Pryde
Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. t.smart@ucl.ac.uk.
Trevor G
TG
Smart
Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. j.r.baker@ucl.ac.uk.
James R
JR
Baker
D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D058787:GABA-A Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism
D001391:Azo Compounds; D058787:GABA-A Receptor Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; C049853:gabazine