The Pharmacology of the Novel and Selective Sigma Ligand, PD 144418

The Pharmacology of the Novel and Selective Sigma Ligand, PD 144418 The pharmacology of PD 144418 (1-propyl-5-(3- p -tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (σ 1 and σ 2 , respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with ( 3 H)(+)-pentazocine and neuroblastoma × glioma cell membranes using ( 3 H)1,3-di- o -tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for σ 1 of 0.08 nM ( K i ) versus a K i of 1377 nM for σ 2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N -methyl- d -aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that σ 1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other σ ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective σ 1 agent, devoid of any significant affinity for other receptors and that σ 1 site may modulate actions in the CNS. © 1997 Elsevier Science Ltd. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuropharmacology Elsevier

The Pharmacology of the Novel and Selective Sigma Ligand, PD 144418

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Publisher
Elsevier
Copyright
Copyright © 1997 Elsevier Science Ltd
ISSN
0028-3908
eISSN
1873-7064
DOI
10.1016/S0028-3908(96)00161-X
Publisher site
See Article on Publisher Site

Abstract

The pharmacology of PD 144418 (1-propyl-5-(3- p -tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (σ 1 and σ 2 , respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with ( 3 H)(+)-pentazocine and neuroblastoma × glioma cell membranes using ( 3 H)1,3-di- o -tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for σ 1 of 0.08 nM ( K i ) versus a K i of 1377 nM for σ 2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N -methyl- d -aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that σ 1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other σ ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective σ 1 agent, devoid of any significant affinity for other receptors and that σ 1 site may modulate actions in the CNS. © 1997 Elsevier Science Ltd. All rights reserved.

Journal

NeuropharmacologyElsevier

Published: Jan 1, 1997

References

  • Blockade by sigma site ligands of high voltage-activated Ca 2+ channels in rat and mouse cultured hippocampal pyramidal neurones
    Church, J; Fletcher, E
  • Motor effects of two sigma ligands mediated by nigrostriatal dopamine neurons
    Goldstein, S.R; Matsumoto, R.R; Thompson, T.L; Patrick, R.L; Bowen, W.D; Walker, J.M
  • Subjective effects of narcotic antagonists cyclazocine and nalorphine on the addiction research center inventory (ARCI)
    Haertzen, C.A
  • The attractions of proteins for small molecules and ions
    Scatchard, G
  • A simple and reliable conflict procedure for testing anti-anxiety agents
    Vogel, J.R; Clody, D.E

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