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The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites.
Mol Pharmacol 1989; 36(6):887-96MP

Abstract

Numerous studies have now demonstrated that a binding site for the psychotomimetic drug phencyclidine (PCP) exists within the receptor channel complex for the excitatory amino acid neurotransmitter glutamate, specifically the glutamate receptor selectively activated by N-methyl-D-aspartate (NMDA). Several lines of evidence support the hypothesis that all PCP receptors in rat brain are associated with the NMDA receptor complex. In the present study, we reexamine this hypothesis. We report that the PCP analog [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [(3H]TCP) labels two high affinity binding sites in membranes prepared from guinea pig brain site 1 (Kd = 14.1 nM, Bmax = 631 fmol/mg of protein) and site 2 (Kd = 46.5 nM, Bmax = 829 fmol/mg of protein). (+)-5-Methyl-10 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate bound to site 1 with high affinity (Kl = 3.2 nM) and to site 2 with low affinity (Kl = 5208 nM). The order of potency of drugs for inhibiting [3H]TCP binding to site 1 correlated with their ED50 values for inhibition of NMDA-mediated responses reported in the literature, whereas the order of potency of drugs for inhibiting [3H]TCP binding to site 2 correlated with their ED50 values for inhibition of [3H]dopamine reuptake reported in the literature. Kinetic experiments demonstrated that glutamate, 2-amino-7-phosphonoheptanoic acid, and Mg2+ modulated [3H]TCP binding to site 1 but not site 2. Preincubation of guinea pig striatal membranes with varying concentrations of the high affinity dopamine reuptake inhibitors N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine caused a wash-resistant inhibition of [3H]TCP binding to site 2 but not site 1. Taken collectively, these data demonstrate the existence of a high affinity PCP binding site associated with the dopamine reuptake carrier and raise the possibility that the therapeutic and psychotomimetic effects of PCP in humans are separable and mediated via different binding sites.

Authors+Show Affiliations

Unit on Receptor Studies, LCS, National Institute of Mental Health, Bethesda, Maryland 20892.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

2557536

Citation

Rothman, R B., et al. "The Psychotomimetic Drug Phencyclidine Labels Two High Affinity Binding Sites in Guinea Pig Brain: Evidence for N-methyl-D-aspartate-coupled and Dopamine Reuptake Carrier-associated Phencyclidine Binding Sites." Molecular Pharmacology, vol. 36, no. 6, 1989, pp. 887-96.
Rothman RB, Reid AA, Monn JA, et al. The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites. Mol Pharmacol. 1989;36(6):887-96.
Rothman, R. B., Reid, A. A., Monn, J. A., Jacobson, A. E., & Rice, K. C. (1989). The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites. Molecular Pharmacology, 36(6), pp. 887-96.
Rothman RB, et al. The Psychotomimetic Drug Phencyclidine Labels Two High Affinity Binding Sites in Guinea Pig Brain: Evidence for N-methyl-D-aspartate-coupled and Dopamine Reuptake Carrier-associated Phencyclidine Binding Sites. Mol Pharmacol. 1989;36(6):887-96. PubMed PMID: 2557536.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites. AU - Rothman,R B, AU - Reid,A A, AU - Monn,J A, AU - Jacobson,A E, AU - Rice,K C, PY - 1989/12/1/pubmed PY - 1989/12/1/medline PY - 1989/12/1/entrez SP - 887 EP - 96 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 36 IS - 6 N2 - Numerous studies have now demonstrated that a binding site for the psychotomimetic drug phencyclidine (PCP) exists within the receptor channel complex for the excitatory amino acid neurotransmitter glutamate, specifically the glutamate receptor selectively activated by N-methyl-D-aspartate (NMDA). Several lines of evidence support the hypothesis that all PCP receptors in rat brain are associated with the NMDA receptor complex. In the present study, we reexamine this hypothesis. We report that the PCP analog [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [(3H]TCP) labels two high affinity binding sites in membranes prepared from guinea pig brain site 1 (Kd = 14.1 nM, Bmax = 631 fmol/mg of protein) and site 2 (Kd = 46.5 nM, Bmax = 829 fmol/mg of protein). (+)-5-Methyl-10 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate bound to site 1 with high affinity (Kl = 3.2 nM) and to site 2 with low affinity (Kl = 5208 nM). The order of potency of drugs for inhibiting [3H]TCP binding to site 1 correlated with their ED50 values for inhibition of NMDA-mediated responses reported in the literature, whereas the order of potency of drugs for inhibiting [3H]TCP binding to site 2 correlated with their ED50 values for inhibition of [3H]dopamine reuptake reported in the literature. Kinetic experiments demonstrated that glutamate, 2-amino-7-phosphonoheptanoic acid, and Mg2+ modulated [3H]TCP binding to site 1 but not site 2. Preincubation of guinea pig striatal membranes with varying concentrations of the high affinity dopamine reuptake inhibitors N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine caused a wash-resistant inhibition of [3H]TCP binding to site 2 but not site 1. Taken collectively, these data demonstrate the existence of a high affinity PCP binding site associated with the dopamine reuptake carrier and raise the possibility that the therapeutic and psychotomimetic effects of PCP in humans are separable and mediated via different binding sites. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/2557536/The_psychotomimetic_drug_phencyclidine_labels_two_high_affinity_binding_sites_in_guinea_pig_brain:_evidence_for_N_methyl_D_aspartate_coupled_and_dopamine_reuptake_carrier_associated_phencyclidine_binding_sites_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2557536 DB - PRIME DP - Unbound Medicine ER -