indiplon and zaleplon

Insomnia is a prevalent problem in late life. Sleep problems in the elderly are often mistakenly considered a normal part of aging. Insomnia, the most common sleep disorder, is a subjective report of insufficient or nonrestorative sleep despite adequate opportunity to sleep. Despite the fact that more than 50% of elderly people have insomnia, it is typically undertreated, and nonpharmacologic interventions are underused by health care practitioners. This article will review the causes of insomnia in the elderly, the approach to patient evaluation, and the nonpharmacologic and pharmacologic treatment of insomnia.

Topics: Acetamides; Aged; Aging; Antidepressive Agents; Azabicyclo Compounds; Behavior Therapy; Benzodiazepines; Humans; Hypnotics and Sedatives; Nonprescription Drugs; Piperazines; Pyridines; Pyrimidines; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Sleep; Sleep Initiation and Maintenance Disorders; Sleep, REM; Thiophenes; Trazodone; Zolpidem

Clinically used benzodiazepine and nonbenzodiazepine sedative-hypnotic agents for the treatment of insomnia produce their therapeutic effects through allosteric enhancement of the effects of the inhibitory neurotransmitter GABA at the GABA(A) receptor. Indiplon is a novel pyrazolopyrimidine sedative-hypnotic agent, currently in development for insomnia. Using radioligand binding studies, indiplon inhibited the binding of [(3)H]Ro 15-1788 (flumazenil) to rat cerebellar and cerebral cortex membranes with high affinity (K(i) values of 0.55 and 0.45 nM, respectively). [(3)H]Indiplon binding to rat cerebellar and cerebral cortex membranes was reversible and of high affinity, with K(D) values of 1.01 and 0.45 nM, respectively, with a pharmacological specificity consistent with preferential labeling of GABA(A) receptors containing alpha1 subunits. In "GABA shift" experiments and in measurements of GABA-induced chloride conductance in rat cortical neurons in culture, indiplon behaved as an efficacious potentiator of GABA(A) receptor function. In both the radioligand binding and electrophysiological experiments, indiplon had a higher affinity than zolpidem or zaleplon. These in vitro properties are consistent with the in vivo properties of indiplon as an effective sedative-hypnotic acting through allosteric potentiation of the GABA(A) receptor.

Topics: Acetamides; Animals; Azides; Benzodiazepines; Binding Sites; Brain; Cell Membrane; Cerebellum; Cerebral Cortex; Chloride Channels; Flumazenil; GABA Modulators; gamma-Aminobutyric Acid; Kinetics; Male; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Thiophenes; Triazolam; Tritium; Zolpidem

Topics: Acetamides; Age Factors; Azabicyclo Compounds; Benzodiazepines; Humans; Hypnotics and Sedatives; Piperazines; Pyridines; Pyrimidines; Sleep Wake Disorders; Thiophenes; Trazodone; Zolpidem