Psych Exam 2 Drug Design: CNS Depressants (Vino)

subtypes of subunits of GABA

· 6 types of alpha subunits

· 3 beta subunits

· Three gamma subunits

· Single sigma, epsilon, pi, and theta subunits

subunit combo of most GABA receptors

a1-B2-y2

bidning site of benzodiazepines on GABA

· extracellular N-terminus of alpha 1,2, 3, and 5 subunits for benzos

GABA alpha 1 subunit fuction

required for sedative + hypnotic effects

GABA alpha 2 subunit function

anxiolytic effects

GABA alpha 4 + 6 subunit function

insensitive to classical 1.4 BZDs

GABA gamma-2 subunit function

needed for best positive allosteric effect

what happens when a BZD binds to GABA-AR

this increases the affinity of GABA for the receptor which increases the frequency of ion channel opening

net result in hyperpolarization of the membrane

factors of efficiency of a hypnotic drug

o development of acute tolerance to BZD before it's eliminated from CNS

o redistribution from CNS to other tissues

o drug elimination

SAR of first-generation BZDs

· : 1-N and 2-carbonyl function are optimal for activity

which BZDs are 2nd gen and how do they differ?

o Triazolam and estazolam

o High receptor binding affinity and rapid elimination (eliminates drowsiness)

general properties of BZDs

lipophilic so rapidly absorbed

where do barbiturates bind on GABA-AR

bind to an allosteoc recognition site

effect of barbiturates when they bind to GABA-AR

· GABA mimetic effect: can increase Cl ion influx without GABA attaching to the receptor

SAR of barbiturates

· 5,5 disubstitution

o Both protons at 5 position must be replaced for activity and duration of action

ramelteon, where does it bind and what does it do?

binds to MT1 only and helps initiate sleep

which BZDs are class A?

§ Clonazepam

§ Clorazepam

§ Diazepam

§ Flurazepam

§ Halazepam

§ Lorazepam

§ Oxazepam

§ temazepam

which BZDs are class B?

§ Alprazolam

§ Estazolam

§ Midazolam

which drugs are serotonin receptor-active agents

busprione (partial agonist, SSRIs, SNRIs)

BZD ring A SAR

· replacing ring A with a heterocycle reduces activity

o Electronegative group (halogen or nitro) at C7 increases anxiolytic activity

o C6, C8, C9 substituents decrease anxiolytic anxiety

BZD ring B SAR

o Presence of proton-accepting grouop is needed

o For optimal affinity should be in coplanar spatial orientation with ring A

o Substitution of sulfur for oxygen at C2 may affect the selectivity of binding to receptor but the anxiolytic activity is maintained

o Sub at C3 or imine nitrogen is unfavorable for antagonist activity but doesn’t have affect on anxiolytic activity

BZD ring C SAR

o not required for binding but may increase affinity to receptor due to favorable hydrophobic interactions

o sub at 4' (para) decreases activity

which drugs are inhaled general anesthetics?

o ether

o halothane

o desflurane

o enflurane

o isoflurane

o methoxyflurane

o sevoflurane

o nitrous oxide

usually halogenated

which drugs are IV general anestehtics?

o etomidate

o ketamine

o propofol

o fospropofol

o thiopental

general anesthetic defintion

drugs that bring reversible loss of consciousness

MAC (minimum alveolar concentration)

o 1 MAC is the concentration necessary to produce immobility in 50% of adult population

o 1.3 MAC causes immobility in 99% population

o Measure of potency

o When used together, MACs of inhaled anesthetics are additive