Abstract | UNLABELLED: EXPERIMENTAL APPROACH: The affinities of these compounds for the D(2) dopamine receptor were evaluated in competition with [(3) H] spiperone and [(3) H]NPA. Agonist activity of these compounds was evaluated in terms of their ability to stimulate [(35) S]GTPγS binding. KEY RESULTS: Both compounds had low affinities for inhibition of [(3) H] spiperone binding (pK(i) vs. [(3) H] spiperone, ACR16: <5, OSU6162: 5.36). Neither compound was able to stimulate [(35) S]GTPγS binding when assayed in the presence of Na(+) ions, but if the Na(+) ions were removed, both compounds were low-affinity, partial agonists (E(max) relative to dopamine: ACR16: 10.2%, OSU6162:54.3%). Schild analysis of the effects of OSU6162 to inhibit dopamine-stimulated [(35) S]GTPγS binding indicated Schild slopes of ∼0.9, suggesting little deviation from competitive inhibition. OSU6162 was, however, able to accelerate [(3) H]NPA dissociation from D(2) dopamine receptors, indicating some allosteric effects of this compound. CONCLUSIONS AND IMPLICATIONS: The two phenylpiperidines were low-affinity, low-efficacy partial agonists at the D(2) dopamine receptor in vitro, possibly exhibiting some allosteric effects. Comparing their in vitro and in vivo effects, the in vitro affinities were a reasonable guide to potencies in vivo. However, the lack of in vitro-in vivo correlation for agonist efficacy needs to be further addressed. LINKED ARTICLES: This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.
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Authors | Elodie Kara, Hong Lin, Kjell Svensson, Anette M Johansson, Philip G Strange |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 161
Issue 6
Pg. 1343-50
(Nov 2010)
ISSN: 1476-5381 [Electronic] England |
PMID | 20804495
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society. |
Chemical References |
- Dopamine Agonists
- Piperidines
- Receptors, Dopamine D2
- OSU 6162
- pridopidine
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Topics |
- Animals
- CHO Cells
- Cricetinae
- Cricetulus
- Dopamine Agonists
(administration & dosage, metabolism, pharmacology)
- Humans
- Piperidines
(administration & dosage, metabolism, pharmacology)
- Protein Binding
(drug effects, physiology)
- Receptors, Dopamine D2
(agonists, metabolism)
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