Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interactions of the hallucinogenic drug PCP [1-(1-phenylcyclohexyl)piperidine] and some of its analogs with the nicotinic acetylcholine receptor-ionic channel complex were studied using electrophysiological techniques. The peak amplitude and the decay time constant of the nerve-evoked end-plate current (EPCs) recorded from the frog sartorius muscle were reduced by all the analogs in a concentration-dependent manner (IC50 between 5 and 90 microM). PCP, TCP [1-[1-(2-thienyl)cyclohexyl]-piperidine] and PCE (N-ethyl-1-phenylcyclohexylamine), among other analogs, caused a negative slope conductance in the current-voltage relationship at hyperpolarized potentials and a voltage- and time-dependent depression of the peak amplitude of the EPC. When the piperidine ring of the PCP molecule was substituted by a morpholino ring, as in 1-(1-phenylcyclohexyl)morpholine and 1-[1-(2-thienyl)-cyclohexyl]morpholine, the potency decreased and the negative conductance was eliminated. The removal of the piperidine ring of PCP in 1-phenylcyclohexylamine and the hydroxylation of the cyclohexane ring in 4-phenyl-4-piperidino-cyclohexanol reduced the potency and produced double exponential decays at potentials between +50 and -50 mV. At -100 mV, the potency for decreasing peak EPC amplitude was well correlated with the potency for reducing the decay time constant for all the analogs. The voltage- and time-dependent depression of the EPC amplitude was reduced by substitution of a morpholino ring and by the elimination of the piperidine ring of PCP. The behaviorally active analogs were the most potent EPC blockers, which suggests a synaptic role for the production of depressant behavioral effects observed with PCP.
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PMID:Effects of phencyclidine and its analogs on the end-plate current of the neuromuscular junction. 348 35

The actions of the tertiary local anesthetic bupivacaine were studied on the nicotinic receptor-ionic channel complex (AChR) using electrophysiological and biochemical methods. Voltage clamp studies of the frog sartorius and cutaneous pectoris neuromuscular junction revealed a concentration-dependent depression of the decay time constant of the end-plate (tau EPC) and spontaneous miniature end-plate (tau MEPC) currents. The relationship of the reciprocal of either tau EPC or tau MEPC and bupivacaine concentration up to 100 microM was linear. Voltage dependence of EPC over the range +60 to -150 mV was reduced, whereas both EPC and MEPC decays were adequately described by a single exponential function at all concentrations tested. Peak MEPC and EPC amplitudes were also depressed in a concentration-dependent manner such that 100 microM bupivacaine reduced peak amplitude by about 50%. The current-voltage relationship remained linear under all conditions tested. Nerve-evoked responses were difficult to study at concentrations greater than 100 microM because of apparent blockade of nerve conduction. Extracellular recording of the MEPC afforded results similar to those obtained with EPCs. The tau MEPC could be reduced to less than 300 mu sec at a bupivacaine concentration of 400 microM. Fluctuation analysis showed that bupivacaine at concentrations of 10 and 25 microM did not change channel conductance but decreased single-channel lifetime to 76% and 39% of control values, respectively. Biochemical studies were performed on Torpedo californica membrane fragments using [3H]phencyclidine ([3H]PCP) and [3H]perhydrohistrionicotoxin ([3H]H12-HTX) as channel probes. Bupivacaine inhibited the binding of [3H]PCP and [3H]H12-HTX with inhibition constants (Ki) of 32 and 25 microM, respectively. The corresponding inhibition constants for bupivacaine methiodide were 1.8 and 3.2 microM. The preincubation of the membranes with carbamylcholine increased the affinity of bupivacaine for the ionic channel sites 5- to 8-fold and the affinity of bupivacaine methiodide 3- to 4-fold. Bupivacaine, however, had no affinity for the agonist recognition site as determined by [3H]ACh and [125I]alpha-bungarotoxin bindings. The electrophysiological and biochemical studies indicate that bupivacaine reacts primarily with the ionic channel of the nicotinic AChR. The results are consistent with a sequential model in which the drug interacts with the sites at the ionic channel of AChR in its open conformation, producing species with little or no conductance. From the present studies there is no evidence for an interaction of bupivacaine with the agonist binding site or closed states of AChR.
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PMID:Interactions of bupivacaine with ionic channels of the nicotinic receptor. Electrophysiological and biochemical studies. 609 Aug 84