Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of phencyclidine (PCP) related analogs, carbonitrile synthetic precursors and two monohydroxylated metabolites were compared pharmacologically in mice for their ability to produce ataxia using the rotarod method and toxicologically for their acute 4-hr lethality. The slope of the PCP dose-ataxic response curve was steeper than those of diazepam, pentobarbital, morphine and ketocyclazocine but not the slope of the sigma agonist, N-allylnormetazocine curve. Responses for all analogs, metabolites and precursors produced curves parallel to that of PCP. Ataxia potencies of all PCP-related compounds ranged from 0.05 to 2.15 X PCP and durations of action ranged from 18 to 65 min. N-ethyl-1-phenylcyclohexylamine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine and 1-[1-(2-thienyl)-cyclohexyl]-pyrrolidine were most potent and least potent were 1-(1-phenyl-cyclohexyl)-4-methylpiperidine, the phenyl and thienyl morpholines and 4-phenyl-4-piperidinocyclohexanol. Among the PCP analogs, modifying the piperidine or aromatic ring effected changes only in potency. Seizures and respiratory depression characterized the lethal effects of PCP, its analogs, metabolites and precursors. However, the precursors failed to elicit the stereotyped movements and hyperactivity that preceded seizures produced by the other compounds. Overall potencies for lethality relative to PCP covered a narrow range (0.16-1.83) with the carbonitrile precursors being most potent. Therapeutic indices indicated relatively large margins of safety for 1-[1-(2-thienyl)-cyclohexyl]-piperidine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine, N-ethyl-1-phenylcyclohexylamine and ketamine and the smallest were for 1-(1-phenylcyclohexyl)-4-methylpiperidine, the metabolite 4-phenyl-4-piperidinocyclohexanol and the three precursors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phencyclidine analogs and precursors: rotarod and lethal dose studies in the mouse. 674 25

Eighty-four of 147 piglets from 20 purebred Hampshire gilts that were bred to purebred Hampshire boars and then fed Nicotiana glauca during various periods of gestation were congenitally deformed. The deformities occurred in piglets from gilts on experiments in 3 separate years during which 4 different collections of the plant were fed. The deformities included various arthrogrypotic limb deviations and palate closure defects. Arthrogrypotic limbs had excessive flexure of pastern or carpal joints, medial rotation, or a combination of these effects. There were no gross visceral defects nor histopathologic changes in examined tissue. Expression of deformities varied as a function of gestation period. Palate closure defects, for example, occurred only in offspring from sows fed prior to gestation day 35. The limb deformities induced by N. glauca in piglets were similar to those reported by others and assumed, or known from feeding trials, to have been induced by maternal Nicotiana tabacum stalk ingestion. By contrast palate defects were not reported in piglets from maternal N. tabacum ingestion, but were of high incidence in the present work from maternal N. glauca ingestion. The suspect teratogen, anabasine, the principle piperidine alkaloid of N. glauca, varied in concentration among the collections fed. However dosages were maintained in each animal regardless of collection fed that resulted in daily toxicity signs indicative of anabasine toxicosis. The signs included depression, tremors, third eyelid closure, irregular gait and recumbency.
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PMID:Congenital deformities in swine induced by wild tree tobacco, Nicotiana glauca. 688 99

CNS activity of thalidomide was compared with that of 5 analogs modified in the phthalimide or 2,6-dioxopiperidine moiety. All compounds had a qualitatively comparable profile of CNS-depressant actions. In low dosages spontaneous motor activity was depressed, threshold of barbiturate anaesthesia was lowered, and isolation-induced aggression was inhibited. All compounds suppressed tonic convulsions induced by maximum electroshock. Only at high dosages muscle tone and body temperature were lowered. Protection against nicotine lethality revealed antagonistic activity at central nicotinergic synapses. Corresponding depression of peripheral ganglionic transmission was indicated by mydriatic and antidiarrhoeal activity. While thalidomide, supidimide, EM 8, and EM 255 did not induce anaesthesia up to highest or lethal-toxic doses, EM 136 and EM 12 in accordance with common sedative-hypnotic drugs induced loss of righting reflex at high dosages. EM 136 differs from thalidomide only in that one oxygen group at the piperidine moiety is missing. This finding indicates that a minor structural change shifts CNS depression towards anaesthetic properties. A clearcut relation between structure and teratogenic activity had been established in this group of compounds, whereas CNS-depressant efficacy could not be unequivocally related to particular structural features.
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PMID:[Studies on the CNS activity profile of thalidomide analogs (author's transl)]. 720 66

In dogs and rabbits anesthetized with pentobarbital sodium or urethane, respectively, the gastric mucosal blood flow was measured by the thermoelectrical method after intravenous administration of 3-(3, 4, 5-trimethoxybenzamido)piperidine(KU-54), an antiulcer drug. In the gastric corpus of rabbits, the maximal mucosal blood flow (11.9%) was attained within 1 min after KU-54(5 mg/kg i.v.) dosing and there was a prolonged increase during 8 min. Administration of KU-54 produced a transitory depression of the blood pressure by about 20%, and induced a beta-adrenergic-like action, presumably because both the blood pressure depression and the gastric mucosal blood flow increment were simultaneous in rabbits. This phenomenon was however, not abolished by pretreatment with propranolol, a beta-adrenergic blocker, therefore KU-54 may not be a beta-adrenergic blocking agent. Administration of gefarnate, a standard antiulcer drug, produced a slight increase in gastric mucosal blood flow and response to this drug was less than that seen with KU-54. Sulpiride, a standard antiulcer drug, two peaks on the gastric mucosal blood flow increment in rabbits and the pattern of blood flow increment differed from that seen with KU-54. The increment of gastric mucosal blood flow produced by KU-54 (5 mg/kg i.v.) was more successive in the gastric antrum than that in the gastric corpus. In fasting rabbits, the main period of gastric mucosal blood flow increment produced by KU-54 (5 mg/kg i.v.) was more successive than that seen in the non-fasting animals. In dogs, the maximal blood flow (16%) was observed at 7 min after KU-54 (5 mg/KG i.v.) dosing and there was a prolonged increase during 6 min.
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PMID:[Influence of 3-(3, 4, 5-trimethoxybenzamido) piperidine (KU-54) on gastric mucosal blood flow (author's transl)]. 720 76

Urinary excretion of piperidine, a heterocyclic pressor amine of gut bacterial origin and nicotine-like activity in the brain, has been estimated by a gas chromatography method in healthy men and women, in normal breast-fed and formula-fed infants and in infants with untreated coeliac disease. The excretion of piperidine cannot usually be detected during the first week of life. The amount present in urine increases upon weaning with higher excretion in formula-fed than in breast-fed infants at four to six months of age. When premature infants fed on human milk are weaned, the urinary content of piperidine rises from undetectable amounts to normal for age. The high content present in untreated coeliac disease may be responsible for the initial mental depression commonly seen in this disease and suggests that piperidine is one of the "auto-intoxicating" substances arising from the bacterial decomposition of protein postulated by Metchnikoff in 1903 but hitherto unidentified.
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PMID:Increased excretion of a brain depressor amine in infantile coeliac disease and in healthy infants on a high protein milk diet. 723 85

Piperidine is one of the biogenic amines possessing potent pharmacological activity. Recent interest has focused on its possible role as an endogenous hypnogenic substance. Using a mass fragmentographic technique with deuterium-labelled piperidine as an internal standard, piperidine concentrations in brains of waking and deeply anesthetized mice were analyzed to compare piperidine levels in the brain under distinctly different states of consciousness. A rapid and significant increase in piperidine concentrations was found in the brain but not in blood of mice anesthetized with any one of pentobarbital, urethane, ether and halothane. The results, showing that CNS depression is accompanied by accumulation of piperidine in the brain, are consistent with the idea that piperidine may have a close connection with the mechanisms controlling the level of consciousness.
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PMID:Effects of anesthetics on piperidine levels in mouse brain. 723 88

Bath application of the muscarinic receptor agonist, muscarine, produced a concentration-dependent depression of synaptic activity in the dentate gyrus of hippocampal slices. A concentration of 10 microM muscarine produced a reversible depression that could be competitively antagonized by the muscarinic receptor antagonist pirenzepine. However, other muscarinic receptor subtype (M1-M3) antagonists could also block the effects of muscarine. The rank order of antagonist potency was: 4-diphenylacetoxy-N-methyl-piperidine methiodide (M3/M1 antagonist) > pirenzepine (M1) > AFDX-116 (M2). The depression produced by 10 microM muscarine was not affected by in vivo pretreatment with pertussis toxin, and therefore was not mediated by a pertussis toxin-sensitive G-protein. In addition, high concentrations of muscarine did not affect either basal or isoproterenol-stimulated accumulation of cyclic AMP from slices of dentate gyrus. Muscarine also produced a concentration-dependent blockade of the induction of norepinephrine-induced long-lasting potentiation in the dentate gyrus. Norepinephrine-induced long-lasting potentiation is a form of long-lasting plasticity induced in medial perforant path synapses by beta-adrenergic agonists such as isoproterenol. The muscarinic blockade of norepinephrine-induced long-lasting potentiation was also prevented by pretreatment with pirenzepine. Based on these pharmacological data, we conclude that muscarinic depression of evoked responses, as well as blockade of norepinephrine-induced long-lasting potentiation, involves activation of either M3 or M1, but not M2, muscarinic receptors. These data also demonstrate that in addition to modulating normal synaptic transmission, muscarinic receptors may also play an important role in modulating synaptic plasticity.
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PMID:Muscarinic depression of synaptic transmission and blockade of norepinephrine-induced long-lasting potentiation in the dentate gyrus. 768 52

Remifentanil is a newly synthesized 4-anilido-piperidine with an ester side chain susceptible to esterase metabolism. We evaluated the safety, analgesic efficacy, and pharmacokinetics of remifentanil in 48 male volunteers. Volunteers were randomized to receive increasing doses of remifentanil, alfentanil, or placebo. Analgesic efficacy was evaluated by increasing tolerance to a spring-loaded rod measured at the tibia and sternum at multiple time points. Respiratory depression was measured by changes in arterial blood gas tensions and peripheral hemoglobin oxygen saturation. Hemodynamics were continuously monitored by means of an intra-arterial catheter. Both remifentanil and alfentanil produced a dose-dependent increase in analgesia and respiratory depression. Remifentanil was 20 to 30 times more potent (milligram to milligram) than alfentanil when assessed by either analgesic efficacy or respiratory measures. The pharmacokinetics of remifentanil were best described by a biexponential decay curve. Remifentanil had a small volume of distribution of 0.39 (SD, +/- 0.25) L/kg (alfentanil, 0.52 +/- 2 L/kg), with a rapid distribution phase of 0.94 (SD, +/- 0.57) min and an extremely short elimination half-life of 9.5 (SD, +/- 4) min compared with an elimination half-life of alfentanil of 58 (SD, +/- 7.6) min. The t1/2 ke0 (half-time for equilibration between plasma and the effect compartment) of remifentanil for analgesia was calculated as 1.3 min. Thus, remifentanil appears to have a pharmacologic profile similar to other potent mu agonists, but with exceptionally short-lasting pharmacokinetics, which is likely to make it a very useful opioid for clinical practice.
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PMID:Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). 1203 62

1. The role of muscarinic M2 and M3 receptors in ileal smooth muscle has been evaluated by use of selective receptor alkylation. The alkylating agents, 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP mustard) was studied for effects against (+)-cis-dioxolane, at muscarinic M2 and M3 receptors in guinea-pig atria or ileum, respectively. 4-DAMP mustard (10 nM, 40 min exposure) did not discriminate between these muscarinic receptors. In ileum, 4-DAMP mustard, at 100 nM, resulted in a large dextral shift (197 fold) and depression in maxima. In atria there was a smaller dextral shift (14 fold) but no depression in maxima. 2. The muscarinic antagonists, atropine (non-selective), methoctramine (M2-selective) and para-fluorohexahydro-siladiphenidol (pFHHSiD; M3 selective) were studied in protection studies against alkylation by phenoxybenzamine. Washout studies following equilibration of the tissues with atropine (30 nM), methoctramine (0.3 microM) or pFHHSiD (3 microM), showed the compounds to be reversible. No temporal changes in sensitivity to (+)-cis-dioxolane were observed. 3. Exposure, for 20 min, of atria and ileum to phenoxybenzamine (3 and 10 microM respectively) caused dextral shifts and depressions in the maxima of the concentration-response curve to (+)-cis-dioxolane. These effects were inhibited by prior equilibration with atropine (30 nM) and methoctramine (0.1 microM) in atria or atropine (30 nM) and pFHHSiD (3 microM) in ileum. Similar results in ileum were obtained when pilocarpine was used as the agonist. 4. These data were consistent with muscarinic M2 receptors mediating responses in atria and M3 receptors mediating responses in ileum. No evidence was provided for a direct role of muscarinic M2 receptors in ileal contraction.5. It is concluded that receptor protection by reversible antagonists for muscarinic M2 or M3 receptors provides a means to isolate pharmacologically a single subtype in a tissue possessing heterogeneous populations. This technique may prove useful in defining the role of the respective subtypes in smooth muscle contraction.
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PMID:Selective inactivation of muscarinic M2 and M3 receptors in guinea-pig ileum and atria in vitro. 840 47

A-3665 is a new short-acting synthetic opioid of the piperidine class. We conducted a double-blind, escalating dose comparison of A-3665 to alfentanil and placebo. Analgesic efficacy was assessed after the administration of A-3665 in increasing intravenous doses (0.25, 0.5, 1, 2, 4, 8, 16, 32, and 64 micrograms/kg) to nine groups of volunteers. At the lower doses (0.25, 0.5, 1, and 2 micrograms/kg), five volunteers were in each group; four received A-3665 and one received placebo in a double-blind manner. There were nine volunteers in each of the next three groups; four received A-3665 (4, 8, or 16 micrograms/kg), four received alfentanil (4, 8, or 16 micrograms/kg), and one received placebo. At the 32 micrograms/kg and 64 micrograms/kg dose levels, five subjects each were to be enrolled (four to receive A-3665 and one to receive placebo); however, the study was terminated after two subjects in the 64 micrograms/kg group had significant respiratory depression. Both drugs caused potent analgesia, compared with placebo, with peak effect occurring 3 min after injection. There was no significant difference in analgesic potency of A-3665 and alfentanil as measured by tolerance to tibial pressure at 3 min. At the dose of 16 micrograms/kg, both drugs significantly increased pain tolerance to tibial pressure compared with placebo at 3 min, but alfentanil continued to display significant analgesic effect versus placebo and versus A-3665 at 6, 11, and 15 min after injection. A-3665 caused significant respiratory depression at doses of 32 micrograms/kg and 64 micrograms/kg, but alfentanil did not induce significant respiratory depression at the doses tested.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A-3665, a new short-acting opioid: a comparison with alfentanil. 846 23


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