Aspects of a preclinical GABAaR subtype drug discovery (in vitro)

Question 1

displacement of 3H-flunitrazepam by cold diazepam from rodent brain homogenate, or from cell lines expressing recombinant GABAaRs
what in vitro experiment is used here

Answer 1

radioligand binding

Question 2

what is the IC50

Answer 2

concentration of cold diazepam required to displace 50% of the specific binding of the 3H-flunitrazepam

Question 3

the binding assay is important for information on what

Answer 3

the affinity of the drug for the receptor
and info about whether the drug exhibits binding for a particular GABAaR subtype

Question 4

L828,417 binds to alpha1,alpha2,alpha3,alpha5 - betagamma2 GABAaRs but has no functional effect on what alpha subunit

Answer 4

alpha 1 GABAaRs

Question 5

L828,417 binds to alpha1,alpha2,alpha3,alpha5 - betagamma2 GABAaRs but has no functional effect on alpha1 GABAaRS
It is anxiolytic, ______ but NOT ________

Answer 5

anxiolytic, analgesic but NOT sedative

Question 6

alpha5 IA - efficacy is selective NAM os alpha5 GABAaRs
it enhances ______

Answer 6

cognition

Question 7

assays for drug discovery
provides information on the binding _____ not _______

Answer 7

affinity not efficacy

Question 8

medium throughput electrophysiology
requirement to determine the efficacy of either :

Answer 8

many chemical modifications of the active drug or
screen large chemical libraries of compounds for efficacy

Question 9

L838,417 EXHIBITS FUNCTIONAL SELECTIVITY ACROSS GABAaR SUBTYPES
L838,417 binds similarly to alpha1, alpha2 and alpha5 GABAaRs but does not influence the function of alpha1GABAaRs
I.E
it is a PAM of ____
but a benzodiazepine antagonist of ____

Answer 9

L838,417 is a PAM of alpha2, 3, 5 GABAaRs
but a benzodiazepine antagonist of alpha 1 GABAaRs

Question 10

L838,417 is _____, analgesic, but not _______

Answer 10

L838,417 is anxiolytic, analgesic, but not sedative

Question 11

THE ELECTROPHYSIOLOGICAL PROFILE OF ALPHA5-GABAaRs SELECTIVE INVERSE AGONISTS

L655,708, or alpha5IA, or RO4938581 binds similarly to alpha1, alpha2, alpha3, alpha5 GABAaRs but onlt inhibits function of what alpha GABAaRs

Answer 11

alpha5 GABAaRs

Question 12

THE ELECTROPHYSIOLOGICAL PROFILE OF ALPHA5-GABAaRs SELECTIVE INVERSE AGONISTS

L655,708, or alpha5IA, or RO4938581 binds similarly to alpha1, alpha2, alpha3, alpha5 GABAaRs but onlt inhibits function of alpha5 GABAaRs
I.E
it is a NAM of ______
but is a benzodiazepine antagonist of ____ GABAaRs

Answer 12

NAM of alpha 5 GABAaRs
benzodiazepine antagonist of alpha1, 2 , 3 GABAaRs

Question 13

alpha5 GABAaRs selective NAMs exhibit __________ behavior

Answer 13

pro cognitive

Question 14

alpha GABAaRs selective NAMs exhibit pro cognitive behavior, but distinct from non-selective GABAaR antagonists (bicuculinne) are not pro _____

Answer 14

convulsant