Effects of phencyclidine on cardiac action potential: pH dependence and structure-activity relationships

Gail A. D'Amico; Richard P. Kline; Saul Maayani; Harel Weinstein; Joel Kupersmith

doi:10.1016/0014-2999(83)90578-2

Effects of phencyclidine on cardiac action potential: pH dependence and structure-activity relationships

Gail A. D'Amico, Richard P. Kline, Saul Maayani, Harel Weinstein, Joel Kupersmith

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The effects of phencyclidine [1-(1-phenylcyclohexyl)-piperidine; PCP] on cardiac action potential duration (APD) were compared to those of some of its derivatives, in strips of isolated frog ventricular muscle perfused with normal Ringer solution. We studied compounds with PCP-like behavioral actions (N-ethyl-1-phenyl-cyclohexamine: PCE; and m-amino-PCP) as well as behaviorally inactive analogs (m-nitro-PCP; the quaternary derivative PCP-methyliodide; and various fragments of the PCP molecule). Exposure to PCP, 3 μM to 1 mM, produced reversible, dose- and pH-dependent prolongations, of the APD to over 100% above control. The observed effects of the drugs are compatible with a mechanism of blockade of potassium conductance. An intracellular site for this action is suggested by: (i) the inactivity of the quaternary analog; (ii) the marked increase in the potency of the compounds when the external pH is changed in the region of their respective pK_a values to increase the concentration of the unionized species; and (iii) the pronounced acceleration of the termination of the PCP effect by washout with a series of buffer solutions with decreasing pH values. The rank order of potency of the compounds in lengthening APD (PCE > m-amino PCP > PCP⋙m-nitro-PCP) is the same as reported from other pharmacological studies of specific PCP actions, and matches the rank of behavioral activity of the drugs.

Original language	English
Pages (from-to)	283-290
Number of pages	8
Journal	European Journal of Pharmacology
Volume	88
Issue number	4
DOIs	https://doi.org/10.1016/0014-2999(83)90578-2
State	Published - 8 Apr 1983
Externally published	Yes

Keywords

Action potential
Behavioral effects
Phencyclidine
Potassium channels
Structure-activity relations
pH dependence

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10.1016/0014-2999(83)90578-2

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@article{7dde5e652e7e42e98facda350054e1ca,

title = "Effects of phencyclidine on cardiac action potential: pH dependence and structure-activity relationships",

abstract = "The effects of phencyclidine [1-(1-phenylcyclohexyl)-piperidine; PCP] on cardiac action potential duration (APD) were compared to those of some of its derivatives, in strips of isolated frog ventricular muscle perfused with normal Ringer solution. We studied compounds with PCP-like behavioral actions (N-ethyl-1-phenyl-cyclohexamine: PCE; and m-amino-PCP) as well as behaviorally inactive analogs (m-nitro-PCP; the quaternary derivative PCP-methyliodide; and various fragments of the PCP molecule). Exposure to PCP, 3 μM to 1 mM, produced reversible, dose- and pH-dependent prolongations, of the APD to over 100% above control. The observed effects of the drugs are compatible with a mechanism of blockade of potassium conductance. An intracellular site for this action is suggested by: (i) the inactivity of the quaternary analog; (ii) the marked increase in the potency of the compounds when the external pH is changed in the region of their respective pKa values to increase the concentration of the unionized species; and (iii) the pronounced acceleration of the termination of the PCP effect by washout with a series of buffer solutions with decreasing pH values. The rank order of potency of the compounds in lengthening APD (PCE > m-amino PCP > PCP⋙m-nitro-PCP) is the same as reported from other pharmacological studies of specific PCP actions, and matches the rank of behavioral activity of the drugs.",

keywords = "Action potential, Behavioral effects, Phencyclidine, Potassium channels, Structure-activity relations, pH dependence",

author = "D'Amico, {Gail A.} and Kline, {Richard P.} and Saul Maayani and Harel Weinstein and Joel Kupersmith",

note = "Funding Information: Phencyclidine \[1 -( 1-phenylcyclohexyl)-piperidine; PCP\] exhibits a complex pharmacology derived from the actions of the drug on both the central and peripheral nervous systems (for recent reviews see Petersen and Stillman, 1978; Maayani * This work was supported by USPHS grants DA-02534 and HL-25135 and a grant in aid (No. 80909) from the Ameri-can Heart Association to R.P.K. who also holds an NIH Young Investigation Award (HL 25798). H.W. is recipient of an Irma T. Hirsch Career Scientist Award, and a Re-search Scientist Development Award (K02 DA-00060) from the National Institute on Drug Abuse. G.A.D. was sup-ported by a Predoctoral Training Grant GM-07163 from the National Institute of General Medical Sciences. ** To whom all correspondence should be addressed.",

year = "1983",

month = apr,

day = "8",

doi = "10.1016/0014-2999(83)90578-2",

language = "English",

volume = "88",

pages = "283--290",

journal = "European Journal of Pharmacology",

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T1 - Effects of phencyclidine on cardiac action potential

T2 - pH dependence and structure-activity relationships

AU - D'Amico, Gail A.

AU - Kline, Richard P.

AU - Maayani, Saul

AU - Weinstein, Harel

AU - Kupersmith, Joel

N1 - Funding Information: Phencyclidine \[1 -( 1-phenylcyclohexyl)-piperidine; PCP\] exhibits a complex pharmacology derived from the actions of the drug on both the central and peripheral nervous systems (for recent reviews see Petersen and Stillman, 1978; Maayani * This work was supported by USPHS grants DA-02534 and HL-25135 and a grant in aid (No. 80909) from the Ameri-can Heart Association to R.P.K. who also holds an NIH Young Investigation Award (HL 25798). H.W. is recipient of an Irma T. Hirsch Career Scientist Award, and a Re-search Scientist Development Award (K02 DA-00060) from the National Institute on Drug Abuse. G.A.D. was sup-ported by a Predoctoral Training Grant GM-07163 from the National Institute of General Medical Sciences. ** To whom all correspondence should be addressed.

PY - 1983/4/8

Y1 - 1983/4/8

N2 - The effects of phencyclidine [1-(1-phenylcyclohexyl)-piperidine; PCP] on cardiac action potential duration (APD) were compared to those of some of its derivatives, in strips of isolated frog ventricular muscle perfused with normal Ringer solution. We studied compounds with PCP-like behavioral actions (N-ethyl-1-phenyl-cyclohexamine: PCE; and m-amino-PCP) as well as behaviorally inactive analogs (m-nitro-PCP; the quaternary derivative PCP-methyliodide; and various fragments of the PCP molecule). Exposure to PCP, 3 μM to 1 mM, produced reversible, dose- and pH-dependent prolongations, of the APD to over 100% above control. The observed effects of the drugs are compatible with a mechanism of blockade of potassium conductance. An intracellular site for this action is suggested by: (i) the inactivity of the quaternary analog; (ii) the marked increase in the potency of the compounds when the external pH is changed in the region of their respective pKa values to increase the concentration of the unionized species; and (iii) the pronounced acceleration of the termination of the PCP effect by washout with a series of buffer solutions with decreasing pH values. The rank order of potency of the compounds in lengthening APD (PCE > m-amino PCP > PCP⋙m-nitro-PCP) is the same as reported from other pharmacological studies of specific PCP actions, and matches the rank of behavioral activity of the drugs.

AB - The effects of phencyclidine [1-(1-phenylcyclohexyl)-piperidine; PCP] on cardiac action potential duration (APD) were compared to those of some of its derivatives, in strips of isolated frog ventricular muscle perfused with normal Ringer solution. We studied compounds with PCP-like behavioral actions (N-ethyl-1-phenyl-cyclohexamine: PCE; and m-amino-PCP) as well as behaviorally inactive analogs (m-nitro-PCP; the quaternary derivative PCP-methyliodide; and various fragments of the PCP molecule). Exposure to PCP, 3 μM to 1 mM, produced reversible, dose- and pH-dependent prolongations, of the APD to over 100% above control. The observed effects of the drugs are compatible with a mechanism of blockade of potassium conductance. An intracellular site for this action is suggested by: (i) the inactivity of the quaternary analog; (ii) the marked increase in the potency of the compounds when the external pH is changed in the region of their respective pKa values to increase the concentration of the unionized species; and (iii) the pronounced acceleration of the termination of the PCP effect by washout with a series of buffer solutions with decreasing pH values. The rank order of potency of the compounds in lengthening APD (PCE > m-amino PCP > PCP⋙m-nitro-PCP) is the same as reported from other pharmacological studies of specific PCP actions, and matches the rank of behavioral activity of the drugs.

KW - Action potential

KW - Behavioral effects

KW - Phencyclidine

KW - Potassium channels

KW - Structure-activity relations

KW - pH dependence

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DO - 10.1016/0014-2999(83)90578-2

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JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 4

ER -

Effects of phencyclidine on cardiac action potential: pH dependence and structure-activity relationships

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Keywords

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