CNS-depressant activity

It is interesting to note that some 1,5-benzodiazepines such as 29 also possess CNS depressant activity. Treatment of substituted diphenylamine 26 with methyl malonyl chloride and reduction with Raney nickel led to orthophenylenediamine analogue 27. Sodium alkoxide treatment led to lactam formation (28), and alkylation in the usual way with NaH and methyl iodide produced clobazam (29). °... 

Two novel monoaminodibenzothiophenes, 9b-amino-l,4,4a,9b-tetra-hydrodibenzothiophene (113) and 9b-amino-l,2,3,4,4a,9b-hexayhydro-dibenzothiophene (114) have been synthesized from the corresponding carboxylic acid sulfones 32 and 33 by treatment with sodium methoxide and bromine followed by reduction of the resultant sulfone carbamates with LAH. A -Alkylation of both 113 and 114 gives compounds which possess CNS depressant activity. ... 

The discovery of the sedative/hynoptic activity of derivatives of barbituric acid has led to very extensive dissections of that molecule. One outcome of this work is the realization that acylurea and acylamide derivatives often exhibit CNS depressant activity. A fair number of such molecules have been prepared that contain a succinimide or glutarimide pharmacophore. For example, Michael addition of cyanide to the stereochemically xmdefined cinnamate... 

Slows intestinal motihty Dose Adul. Initial 4 mg PO, then 2 mg aftCT each loose stool, up to 16 mg/d Feds. 2—5 y, 13—20 kg 1 mg PO tid 6-8 y, 20—30 kg 2 mg PO bid 8-12 y, >30 kg 2 mg PO tid Caution [B, +] Not for acute D caused by Salmonella sp, Shigella sp, or C. difficile Contra Pseudomembranous colitis, bloody D Disp Caps, tabs, Liq SE Constipation, sedation, dizziness Interactions t Effects W/ antihistamines, CNS depressants, phenothiazines, TCAs, EtOH EMS Use caution w/ narcotics, may T risk of constipation related to opioids OD May cause constipation and CNS depression activated charcoal may be effective, naloxone (Narcan) may be effective... 

Concurrent EtOH use can T sedation contains anhydrous morphine from opium OD May cause constipation and CNS depression activated charcoal may be effective, naloxone can be used for resp depression... 

JAP77148076). Some other oxathiazoline derivatives (279) have central nervous system (CNS) activity, as tranquilizers and ataraxics with low toxicity (68SAP6804299) and some dioxazoline derivatives (280) have a modest CNS depressant activity (77JPS772). 

Central nervous system (CNS) depressant activity. Ethanol (95%) extract of the seed, administered orally to mice and rats at a dose of 50 mg/kg, was inactive° . 

Mechanism of Action Apiperazine derivative that competes with histamine for receptor sites in the GI tract, blood vessels, and respiratory tract. May exert CNS depressant activity in subcortical areas. Diminishes vestibular stimulation and depresses labyrinthine function. Therapeutic Effect Produces anxiolytic, anticholinergic, antihista-minic, and analgesic effects relaxes skeletal muscle controls nausea and vomiting. Pharmacokinetics ... 

Toxicity results in constipation, GI irritation, including nausea and vomiting, and CNS depression. Activated charcoal is used to treat loperamide toxicity. 

Phase I and II clinical trials indicated that acronycine reduced pain of the spine in some patients with multiple myeloma [280,282,283]. Acronycine has been reported to cause leukopoenia and to have CNS-depressant activity [284], Biochemically, acronycine inhibits incorporation of extracellular nucleosides into the RNA and DNA of leukaemia L-5178Y cell culture. There is, however, no evidence of interaction between acronycine and DNA or inhibition of template activity of DNA. This alkaloid does not inhibit nucleic acid synthesis in the cell, but rather inhibits the accumulation of extracellular uridine or thymidine, as nucleotides, in the intracellular precursor pool [285, 286], Acronycine, acting primarily on membranous organelles [287], seems to interfere with the structure, function and/or turnover of cell membrane components, thereby changing the fluidity of the plasma membrane [288]. 

Certain oxathiazolines are useful ataraxics with low toxicity. An example is the chloroben-zylamine derivative (233) (68SAP6804299). Modest CNS depressant activity has also been found in certain 1,3,4-dioxazolines (234) (77JPS772) and in l,2,3-oxathiazolidin-5-imine S-oxides (235) (77IJC(B)133) (see also Chapter 1.06). 

Isopropanol is a potent central nervous system (CNS) depressant it is believed to exert this effect via a similar mechanism as ethanol by modulating ion transport at the cell membrane in excitatory and inhibitory neurons. Ethanol enhances inhibitory or antagonizes excitatory neurotransmission. The metabolite, acetone, may potentiate and lengthen the duration of CNS symptoms observed upon isopropanol exposure. Although early animal studies suggested that the CNS depressant effects of isopropanol is approximately twice that of ethanol, this increased CNS depressant activity is probably a result of the combined effects of isopropanol and acetone. 

Isopropanol has a short half-life ti ) of 1 to 6 hours, as it is rapidly metabolized by alcohol dehydrogenase to acetone, which is eliminated much more slowly (t]/2,17 to 27 hours), primarily in alveolar air and urine.Therefore concentrations of acetone in serum often exceed those of isopropanol during the elimination phase following isopropanol mgestion (Figure 34-4). Acetone has CNS depressant activity similar to that of ethanol, and because of its longer half-life, it prolongs the apparent CNS effects of isopropanol. 

There was continuing interest in the effects of 3-arylquinazolin-4-ones on the central nervous system (CNS) which resulted from the known activity of methaqualone (117 Ar = o-tolyl R = Me R = H). A most extensive literature is available on the metabolism, pharmacology, and analytical chemistry of methaqualone. The effects of varying the group R on CNS-depressant activity were reported. The structure 117 was associated with CNS-depressant and tranquilizing activities, and 3-o)-aminoalkyl-... 

CNS depressant activity after injection of valepotriates and their degradation products has been documented. A specific valepotriate... 

Valerenic acid, like pentobarbital, decreased performance in both the rotarod and grip tests. The authors concluded that valerenic acid, like pentobarbital, has general CNS depressant activity. Valerenic acid also decreased spontaneous motor activity and prolonged pentobarbital-induced sleeping time. Dose-response effects of valerenic acid were also observed by the investigators. At a dose of 50 mg/kg, a decrease in spontaneous motor activity occurred. At 100 mg/kg, mice exhibited ataxia, then remained motionless. Muscle spasms occurred at 150-200 mg/kg and convulsions at 400 mg/kg, followed by death in six of seven mice within 24 h. 

Studies by Klotz et al. (1975,1976a,b) suggest that biliary excretion of diazepam is unimportant in man, but there is some evidence (see above) for species differences (Klotz etal., 1975,1976a van der Kleijn et al., 1971). Urinary excretion of diazepam is mainly in the form of sulphate and glu-curonide conjugates (Mandelli et al., 1978). The main metabolic pathway is demethylation and hydroxylation to metabolites with CNS depressant activity in animals and man. These metabolites are desmethyldiazepam and oxazepam. 

First-Generation Piperazines. The oldest member of this group, chlorcyclizine, has a more prolonged action and produces a comparatively low incidence of drowsiness. Hydroxyzine is a long-acting compound that is used widely for skin allergies its considerable CNS-depressant activity may contribute to its prominent antipruritic action. Cyclizine and meclizine have been used primarily to counter motion sickness, although promethazine and diphenhydramine (dimenhydrinate) are more effective. 

Substituted pyrrolidines Tinospora cordifolia Miers/ Menisperniaceae Whole plant Hypoglycemic and central nervous system (CNS) depressant activity pyrrolidines in rabbits was observed [17]. 

The steam-distilled oil derived from the galls of Pistacia integerrima was analyzed by chromatography and spectral techniques. The oil was found to be rich in a-pinene (13) (21.8%), P-pinene (14) (16.2%), a-phellandrene (15) (15.5%), and A3-carene (16) (11.1%). The other main constituents characterized were P-phellandrene (17), y-terpinene (18), a-terpineol (19), and P-terpineol (20) as well as a-ocimene (21) and P-ocimene (22). This steam-distilled oil was shown to possess CNS-depressant activity [75]. 

Because it markedly lowers cerebral metabolism, thiopental has been used as a protectant against cerebral ischemia. At least one human study suggests that thiopental may be efficacious in ameliorating ischemic damage in the perioperative setting. Thiopental also reduces intraocular pressure. Perhaps due to their CNS depressant activity, barbiturates are effective anticonvulsants thiopental in particular is effective in the treatment of status epilepticus. 

Meyer and Overton further expanded their theory and suggested that the correlation may be established and observed between lipid solubility and the central nervous system (CNS) depressant aetivity profde. The CNS-depressant activity is foimd to be directly proportional to the partition coefficient of the drug substance . 

In short, the centrally acting muscle relaxants find their abundant application in a plethora of conditions, namely strains and sprains, which may ultimately be responsible for causing acute muscle spasm. Besides, they also particularly possess intemeuronal-blocking characteristics at the level of the spinal cord, which may give rise to the much desired relaxation of the skeletal muscle. Interestingly, most of them exhibit a distinct general CNS-depressant activities. 

---