Validation of GABA(A) receptor subtypes as potential drug targets by using genetically modified mice.
A key issue for drug discovery in the post genomic era is target validation. This is particularly important when considering the CNS, where currently the majority of drug targets are neurotransmitter receptors that are known to exist as multi-gene families. The GABAergic system, which is the major inhibitory neurotransmitter system in the CNS, is no exception in that respect. The GABA(A) receptors, which are the site of action of a number of clinically used drugs such as benzodiazepines and barbiturates, exist in a large gene family. Existing drugs mediating their effects through the GABA(A) receptor are generally non-selective, i.e. will act at several subtypes of that receptor family. Thus, if we are both to refine existing therapeutic approaches, and develop novel approaches, a key question is to define which subtype(s) of the GABA(A) receptor family we should target; which will mediate the beneficial effects of a drug, and which could be responsible for unwanted side effects? One of the tools, which has been developed over the last decade to elucidate the function of a given gene, is the generation and analysis of gene-targeted mice. This review will summarize progress on identifying individual GABA(A) receptor subtypes as potential drug targets by using genetically modified mice.
Rosahl
Thomas W
TW
Merck Sharp & Dohme Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. Thomas_Rosahl@merck.com
D000777:Anesthetics / Q000008:administration & dosage*; D000818:Animals; D030801:Animals, Genetically Modified; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D018755:GABA Agonists / Q000008:administration & dosage; D018756:GABA Antagonists / Q000008:administration & dosage; D018757:GABA Modulators / Q000008:administration & dosage; D018390:Gene Targeting / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000145:classification / Q000187:drug effects* / Q000235:genetics
D000777:Anesthetics; D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D003975:Diazepam