of compounds with affinity for these receptors are not benzodiazepines, it may be more
acceptable to employ the alternative nomenclature:ω 1 for Type I BDZ and ω 2 for Type
II BDZ. The ω 1 receptor is located in brain areas involved with sedation; ω 2 receptors
are highly concentrated in areas responsible for cognition, memory, and psychomotor
functioning. Zolpidem (4.186) was the first non-benzodiazepine ω 1 agonist marketed;
it is a hypnotic agent with minimal anticonvulsant and anxiolytic effects. Zaleplon
(4.187) is another ω 1 agonist used in the treatment of insomnia.
Inverse benzodiazepine agonists such as DMCM (4.188) are anxiogenic and convul-
sive: they are called inverse agonists because they bind to agonist sites but have effects
opposite to those of GABA. Competitive benzodiazepine antagonists (e.g., Ro 15-1788,
4.189) also bind to this site; they are inactive by themselves, but prevent agonist and
inverse agonist binding.
4.7.6 GABAergic Drugs: BarbituratesA large and still used group of these drugs is the barbiturates—sedative-hypnotic
compounds that are used in anesthesia and as “sleeping pills.” Barbiturates are acidic
because of tautomerism with the enolate. Their pKais about 7.3, and therefore even
slight changes in body pH will influence their ionization and, consequently, absorption
and distribution. The replacement of oxygen by sulfur in position 2 leads to increased
lipophilicity and very rapid penetration of the blood–brain barrier. Therefore, com-
pounds like thiopental (4.190) are ultrashort-acting intravenous anesthetics, used in
surgery for short operations or for inducing anesthesia prior to use of inhalation anes-
thetic. Methylation on the N-1 atom has a similar effect, as in hexobarbital (4.191).
Branched side chains on C-5 lead to longer activity (pentobarbital,4.192; and amobar-
bital,4.193); short side chains, like ethyl, lead to the longest duration of action because
NEUROTRANSMITTERS AND THEIR RECEPTORS 277