[Synthesis of 4-acyl-4-(3-chlorophenyl)-1-dialkylaminopropyopropyl)-piperidines. II. Synthesis of 4-acyl-4-(3-chlorophenyl)-1-(3-dialkylaminopropyl)-piperidines].
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Analgesics↗
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Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 5. Conformationally mobile analogues derived by furan ring opening.
Synthesis and antitetrabenazine activity of 4-[2-(arylmethyl)phenyl]piperidines and 4-(benzyloxy)-4-phenylpiperidines, prepared as simplified and possibly more readily synthesized analogues of 3-phenylspiro[isobenzofuran-1 (3H),4'-piperidine], are reported. Several 4-[2-(arylmethyl)phenyl]piperidines display antitetrabenazine activity comparable to imipramine or amitriptyline but are two- to fourfold less active than analogous 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Structure--activity relationships for 4-[2p(arylmethyl)phenyl]piperidines are generally similar to the profile established for 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Significant antitetrabenazine activity is associated only with derivatives where the arylmethyl group is ortho to the piperidine ring. 4-(Benzyloxy)-4-phenylpiperidines and 4-[2-(arylmethyl)phenyl]-4-piperidinols and the corresponding methyl ethers and esters display weak to modest antitetrabenazine activity. 4-[2-(Arylmethyl)phenyl]-1,2,3,6-tetrahydropyridine derivatives, at best, exhibit modest antitetrabenazine activity, with the exception of 4-[2-(phenylmethyl)phenyl]-1,2,3,6-tetrahydropyridine which is approximately equipotent with amitriptyline. The results of these investigations allow certain speculations to be made with respect to the role of the furan ring in the 3-arylspiro[isobenzofuran-1(3H),4'-piperidines] and antitetrabenazine activity.
Animals↗
Metabolites of piperidine in rat urine.
Piperidine is one of pharmacologically active biogenic amines. While two pathways for piperidine production have been reported, little is known about metabolism of the compound. In the present study, piperidine and its hydroxylated, conjugated and unknown metabolites were detected in rat urine by radiochromatographic analysis. Using GC-MS technique, it was confirmed that 3-hydroxypiperidine and 4-hydroxypiperidine are major metabolites of piperidine of either exogenous or endogenous origin. The findings substantiate the existence of a mechanism which inactivates piperidine in the living body, since both metabolites lack the potent pharmacological activities as those induced by piperidine.
Acetylation↗
Actions of piperidine and dimethylphenylpiperazinium (DMPP) on afferent discharges of the cat's carotid body.
Chemoreceptor discharges were recorded in vivo from fine filaments of carotid sinus nerve; their frequency was used as index of receptor activity. Effects of piperidine on chemoreceptors were studied and compared with those of dimethylphenylpiperazinium (DMPP) on chemoreceptors in adult cats. Intracarotid-arterial injections of piperidine produced a transient increase in chemoreceptor discharges, the threshold dose ranging from 10 to 50 microgram i.a. The excitatory effect of piperidine was not affected by atropine, hexamethonium or GABA. DMPP (0.2-0.5 microgram i.a.) induced a marked increase in chemoreceptor discharges, which was abolished by hexamethonium, but not by atropine. DMPP ((2--5 microgram i.a.) induced sinus baroreceptor excitation, but piperidine did not. The results indicate that piperidine exerted excitatory effects on carotid body chemoreceptors, possibly acting on nerve endings of chemoreceptor afferent fibers.
Animals↗
The action of piperidine on muscle spindles in the rat.
Piperidine hydrochloride induced discharge in primary and secondary endings of muscle spindles in rat tailbase muscle preparations. The threshold concentration for primary endings (2.0 X 10(-5) g/ml) was below that for secondary endings (4.0 X 10(-5) g/ml). The effect of piperidine was antagonised by tubocurarine but not by atropine. The action of piperidine on primary and secondary endings responding to 'ramp-and-hold' stretch was predominantly on the static component of excitation, and usually in the absence of any concomitant enhancement of the dynamic effect. This effect was opposite to that induced by succinylcholine. A possible action of piperidine at cholinoceptive sites of the nicotinic type and associated with gamma-trial fusimotor terminals is discussed.
Action Potentials↗
Neurobiology of piperidine: its relevance to CNS function.
Piperidine is a normal constituent in mammalian brain, affects synaptic mechanism in the CNS, and influences neural mechanisms governing regulation of emotional behavior, sleeping, and extrapyramidal function. In addition, there are enzyme systems within the brain that synthesize and metabolize piperidine, and uptake and storage mechanisms for piperidine are found in the nerve endings. In conclusions, piperidine seems to be intimately connected with the neuronal function of the brain.
Animals↗
Characterization of neuromuscular blocking action of piperidine derivatives.
cis and trans forms of 2-methyl-6-n-undecyl piperidines (C-11) are the main constituents of fire ant venom and have been studied for their mechanism of action on the neuromuscular transmission of the nerve-sartorius muscle preparation of frogs. At low concentrations (l times 10(-6)-2 times 10(-5) M), cis- and trans-C-11 irreversibly decreased the amplitude of spontaneous miniature end-plate potentials nerve-evoked end-plate potentials and iontophoretically induced acetylcholine depolarizations without changing the membrane potential. The quantal content and the focally recorded action potentials of nerve terminals remain unchanged. It was concluded that the piperidine derivatives block neuromuscular transmission postsynaptically through a decrease in the sensitivity of the end-plate membrane to acetylcholine. Pretreatment of the end-plate with d-tubocurarine did not effect the blocking action of trans-C-11. In direct binding experiments, trans-C-11 did not compete for the sites occupied by alpha-bungarotoxin, decamethonium, carbamylcholine and d-tubocurarine. These data suggest that trans-C-11 does not bind to the acetylcholine receptor site where the other cholinergic ligands have their affinity. It appears that these piperidine derivatives interfere with the coupling mechanism between acetylcholine-receptor binding and ionic conductance increases.
Acetylcholine↗
Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 4. Central nervous system depressants.
The synthesis of 1'-[3-(4-fluorobenzyoyl)propyl]-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (2a) and eight halo and methoxy analogues is described. The compounds were generally more potent per os than chlorpromazine in the Sidman avoidance paradigm in rats and less potent than haloperido. 1'-[3-(4-Fluorobenzoyl)propyl]-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4'-piperidine] (2e) approached the per os potency of haloperidol in this test and was shown to be active in inhibiting monkey avoidance also. Compound 2e was much less active than haloperidol in antagonizing apomorphine-induced emesis in dogs, apomorphine-induced stereotypy in rats, and amphetamine-induced circling in lesioned rats. This lack of nonselective, dopamine-receptor blocking effects makes 2e attrative as a potential neuroleptic.
Amphetamine↗
Synthesis and stereospecific antipsychotic activity of (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.
The synthesis and resolution of 3-iodocyproheptadine [(+/-)-5a] and 1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine [(+/-)-5b] are described. The resulting atropisomers undergo reaction with trifluoromethylthiocopper to give optically active products without extensive racemization. In this manner, optically pure (+)- and (-)-3-trifluoromethylthiocyproheptadine [(+)-6a and (-)-6a, respectively] and (+)- and (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(+)-6b and (-)-6b, respectively] have been prepared. The influence of a chiral europium shift reagent on the proton and fluorine resonance signals as a diagnostic tool for the determination of the optical purities of these atropisomers is discussed. The four compounds, (+)-6a, (-)-6a, (+)-6b, and (-)-6b, were studied in squirrel monkeys for their ability to block conditioned avoidance responding. All of the antiavoidance activity was found to reside solely in the levorotatory compounds (-)-6a and (-)-6b. Further comparison of the enantiomers (-)-6b and (+)-6b showed that the ability to antagonize apomorphine-induced stereotyped behavior is confined to the levorotatory isomer (-)-6b while weak central anticholinergic activity resides solely in the dextrorotatory isomer (+)-6b. Neither (-)-6b has significant peripheral anticholinergic activity.
Animals↗
Piperidine: effects on locomotor activity and brain monoamine turnover.
The effects of piperidine HCl (PHCl) on locomotor activity, flexor reflex activity and monoamine levels, turnover, and synthesis were studied. Results indicate a sedative action and an increased turnover of noradrenaline (NA), but no effects on 5-hydroxytryptamine (5-HT) or dopamine (DA). Data obtained from flexor reflex experiments suggest that this is not secondary to alpha-adrenergic receptor blockade. One explanation might be an increased impulse activity of NA neurons, but the exact mechanism remains to be elucidated.
Animals↗
Dissociation constants of 4-acetoxy-piperidines and -thiacyclohexanes at the muscarinic receptor.
The dissociation constants (KA) and the relative intrinsic efficacies (e) of 4-acetoxy-piperidines and -thiacyclohexanes were determined on the guinea-pig isolated left atrium. The differences in the muscarinic potencies are associated with differences in affinities and efficacies, respectively.
Acetylcholine↗
Response to the hypobetalipoproteinemic agent adamantyloxyphenyl piperidine in hyperlipemic rats.
The hypobetalipoproteinemic activity of U-41,792 (1-[p-(1-adamantyloxy)-phenyl]-piperidine) is a marked and selective reduction of heparin precipitating lipoproteins (low density plus very low density lipoproteins) in cholesterol-cholic acid induced hypercholesterolemic rats. This activity consists of both a reduction in heparin precipitating lipoproteins (HPL) and an increase in high density lipoproteins that are not precipitated by heparin. The increase in high density lipoproteins is routinely noted by decreases in HPL/cholesterol ratios. The pattern of response following single 100 mg/kg doses of U-418792 was determined. After an I.V. dose was administered in a cottonseed oil emulsion, serum cholesterol levels were reduced, beginning at 8 hr after administration and persisting for 96 hr. Similar results, though delayed somewhat, were obtained after a single oral dose. Activity was accompanied by increases in weight and cholesterol content of livers. After multiple, daily, oral doses, liver weights, total lipids, and cholesterol contents were reduced. Hypobetalipopreteinmeic activity was enhanced by prolonged treatments as demonstrated by analyses of serum obtained weekly throughout 7 wk.
Adamantane↗
Gas-liquid chromatographic determination of 1,3-dihydro-3-phenylspiro(isobenzofuran-1,4-piperidine), HP 505, in biological fluids using a nitrogen-specific detector.
A gas chromatographic method for the determination of 1,3-dihydro-3-phenylspiro[isobenzo-1,4-piperidine], HP 505, in plasma red blood cells and urine has been developed. HP 505 and internal standard are extracted from basified fluid with hexane and then back extracted into acetic acid. After re-extraction into hexane, HP 505 and internal standard are analysed by gas-liquid chromatography as the N-propionyl derivatives using a nitrogen-specific detector. Concentrations of HP 505 can be measured over the range 2-100 ng/ml plasma. The method has been applied to the analysis of biological fluids from volunteers receiving oral doses of HP 505.
Benzofurans↗
Spiro[isobenzofuran-1(3H),4'-piperidines]. 3. Diuretic and antihypertensive properties of compounds containing a sulfur attached to nitrogen.
The synthesis and antihypertensive and diuretic activity of several N-sulfur derivatives of 3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] are reported. Benzenesulfenamide 3 possessed marked, species-specific diuretic and antihypertensive activity in rats.
Animals↗
Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 2. Compounds containing a heteroatom attached to nitrogen.
The synthesis and antitetrabenazine activity of a series of N-heteroatom derivatives of 3-phenylspiro[isobenzofuran-1,4'-piperidines] are reported. Optimal antitetrabenazine activity is associated with compounds containing a sterically unhindered, basic nitrogen. Hydroxylamines 6, 11, 12, and 13 possess the most significant activity with ED50's of 1.4, 3.5, 4.7, and 4.0, respectively.
Animals↗
Antagonism by piperidine of levodopa effects in Parkinson disease.
The nicotinic cholinergic amine piperidine diminished both the dyskinesia and the symptomatic control in some patients with Parkinson disease receiving levodopa. Since the piperdine configuration is contained in the molecules of the apomorphine and N-propylnoraporphine, it might be responsible for the antagonism of these drugs to some effects of levodopa in Parkinson disease and for the palliation by apomorphine of some dopamine-mediated symptoms in other extrapyramidal disorders.
Aged↗
[Isochroman-4-spiro-4'-piperidine: synthesis and analgesic properties].
The synthesis of some isochroman-4-spiro-4'-piperidines by intramolecular O-methylation of 4-aryl-4-hydroxymethylpiperidines with formaldehyde and their analgesic activity ("hot plate"test in mice) are reported. The introduction of the new ring led to compounds with weak analgesic activity.
Analgesics↗
[Structure-activity relationships of piperidine derivatives with aromatic substituents, III (author's transl)].
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Animals↗