Hypnotic activity

Barbituric acid is the parent of a group of compounds known as barbiturates The bar biturates are classified as sedative-hypnotic agents meaning that they decrease the responsiveness of the central nervous system and promote sleep Thousands of deriva lives of the parent ring system of barbituric acid have been tested for sedative-hypnotic activity the most useful are the 5 5 disubstituted derivatives... 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

The wide structural latitude permitted for hypnotic activity is made particularly clear by the observation that the two carbonyl groups in the piperidine ring need not be disposed to form... 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

Values are the means from six separate experiments. SE was less than 10% of the mean. Dose of test compounds, chlorpheniramine maleate and cetirizine are 10 mg/kg for antihistaminic activity, and 5 mg/kg for sedative-hypnotic activity... 

Convulsive disorders are still a serious therapeutic problem and new agents are being actively sought. Classical therapy was based upon the barbiturates that are no longer in favor because of their many side effects and their suicide potential. Interestingly, a seemingly minor structural variation of phenobarbital (152, shown as its sodium salt) leads to an anticonvulsant of increased potency and which has less hypnotic activity. In this case, sodium phenobarbital serves as its own base (so the yield is limited to 50%) and reacts readily with... 

To calculate the hypnotic activity of the compound in rabbits after subcutaveous injection... 

Hansel R, Wagener HH. (1967). [Attempts to identify sedative-hypnotic active substances in hops]. Arzneimittelforschung. 17(1) 79-81. 

Sleep onset latency generally is improved (i.e., shortened) with all BZD hypnotics, although this may vary considerably with individual patients. Those with relatively rapid onset of hypnotic activity include flurazepam, diazepam, and chlorazepate. Somewhat slower onset occurs with triazolam, estazolam, quazepam. 

BZDs with rapid absorption produce a more rapid onset of clinical activity than those with slower absorption. BZDs given orally differ in their speed of absorption from the gastrointestinal tract. For example, absorption time is 0.5 hours for clorazepate, 1 hours for diazepam, 1.3 hours for triazolam, 2 hours for alprazolam and lorazepam, 2 to 3 hours for oxazepam, and 3.6 hours for flurazepam. Absorption, however, may be influenced by the presence or absence of food in the gastrointestinal tract. Thus, patients who take a BZD hypnotic with a bedtime snack may experience a slower onset of hypnotic activity than if the same drug were taken several hours after a meal. 

The benzodiazepines are widely used sedative-hypnotics. All of the structures shown in Figure 22-2 are 1,4-benzodiazepines, and most contain a carboxamide group in the 7-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position. 

C-5 Polar groups Decreased lipophilicity abolished hypnotic activity... 

Silicon Containing Derivatives of Tertiary Alcohols with Sedative-Hypnotic Activity... 

Many benzodiazepines have potent hypnotic activity and are useful in the treatment of insomnia. Examples include flurazepam (Dalmane, A.93), midazolam (Versed, A.94), temazepam (Restoril, A.95), and triazolam (Halcion, A.96) (Figure A.28). Flunitrazepam (Rohypnol, A.97) is a particularly notorious sedative. Often called roofie or the date rape drug, flunitrazepam causes sedation and amnesia. Because of flunitrazepam s tendency to be abused, almost all nations tightly regulate the drug s availability. 

Nicholson AN, Pascoe PA (1986) Hypnotic activity of an imidazopyridine (zolpidem). Brit J Clin Pharmacol 21 205-211... 

Lorizio A, Terzano MG, Parino L et al (1990) Zolpidem a double-blind comparison of the hypnotic activity and safety of a 10-mg versus 20-mg dose. Curr Ther Res 47 889-898... 

Other investigators report silylated amines having antimicrobial (55-57), anticoagulant (55), spasmolytic (55), psychotropic (59), anti-inflammatory, analgesic, sedative, and hypnotic activity, as well as utility in the treatment of peptic ulcers (57). Voronkov reviewed many of these studies (2, 4, 10). 

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