JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Millan, M. J.
Right arrow Articles by Peglion, J.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Millan, M. J.
Right arrow Articles by Peglion, J.-L.

Vol. 287, Issue 1, 167-186, October 1998

S 18126 ({2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl}), a Potent, Selective and Competitive Antagonist at Dopamine D4 Receptors: An In Vitro and In Vivo Comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3b]pyridine) and Raclopride

Mark J. Millan, Adrian Newman-Tancredi, Mauricette Brocco, Alain Gobert, Françoise Lejeune, Valérie Audinot, Jean-Michel Rivet, Rudy Schreiber, Anne Dekeyne, Michael Spedding, Jean-Paul Nicolas and Jean-Louis Peglion

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department (M.J.M., A.N.-T., M.B., A.G., F.L., V.A., J.-M.R., R.S., A.D., M.S., J.-L.P.) and Molecular and Cellualr Pharmacology Department (J.-P.N.), Paris, France

The novel benzoindane S 18126 possessed > 100-fold higher affinity at cloned, human (h) D4 (Ki = 2.4 nM) vs. hD2 (738 nM), hD3 (2840 nM), hD1 (> 3000 nM) and hD5 (> 3000 nM) receptors and about 50 other sites, except sigma 1 receptors (1.6 nM). L 745,870 similarly showed selectivity for hD4 (2.5 nM) vs. hD2 (905 nM) and hD3 (> 3000 nM) receptors. In contrast, raclopride displayed low affinity at hD4 (> 3000 nM) vs. hD2 (1.1 nM) and hD3 receptors (1.4 nM). Stimulation of [35S]-GTPgamma S binding at hD4 receptors by dopamine (DA) was blocked by S 18126 and L 745,870 with Kb values of 2.2 and 1.0 nM, respectively, whereas raclopride (> 1000 nM) was inactive. In contrast, raclopride inhibited stimulation of [35S]-GTPgamma S binding at hD2 sites by DA with a Kb of 1.4 nM, whereas S 18126 (> 1000 nM) and L 745,870 (> 1000 nM) were inactive. As concerns presynaptic dopaminergic receptors, raclopride (0.01-0.05 mg/kg s.c.) markedly enhanced DA synthesis in mesocortical, mesolimbic and nigrostriatal dopaminergic pathways. In contrast, even high doses (2.5-40.0 mg/kg s.c.) of S 18126 and L 745,870 were only weakly active. Similarly, raclopride (0.016 mg/kg i.v.) abolished inhibition of the firing rate of ventrotegmental dopaminergic neurons by apomorphine, whereas even high doses (0.5 mg/kg i.v.) of S 18126 and L 745,870 were only weakly active. As regards postsynaptic dopaminergic receptors, raclopride potently (0.01-0.3 mg/kg s.c.) reduced rotation elicited by quinpirole in rats with unilateral lesions of the substantia nigra, antagonized induction of hypothermia by PD 128,907, blocked amphetamine-induced hyperlocomotion and was effective in six further models of potential antipsychotic activity. In contrast, S 18126 and L 745,870 were only weakly active in these models (5.0-> 40.0 mg/kg s.c.). In six models of extrapyramidal and motor symptoms, such as induction of catalepsy, raclopride was likewise potently active (0.01-2.0 mg/kg s.c.) whereas S 18126 and L 745,870 were only weakly active (10.0-80.0 mg/kg s.c.). In freely moving rats, raclopride (0.16 mg/kg s.c.) increased levels of DA by + 55% in dialysates of the frontal cortex. However, it also increased levels of DA in the accumbens and striatum by 70% and 75%, respectively. In contrast to raclopride, at a dose of 0.16 mg/kg s.c., neither S 18126 nor L 745,870 modified frontal cortex levels of DA. However, at a high dose (40.0 mg/kg s.c.), S 18126 increased dialysate levels of DA (+ 85%) and noradrenaline (+ 100%), but not serotonin (+ 10%), in frontal cortex without affecting DA levels in accumbens (+ 10%) and striatum (+ 10%). In conclusion, S 18126 and L 745,870 behave as potent and selective antagonists of cloned, hD4 vs. other dopaminergic receptor types in vitro. However, their in vivo effects at high doses probably reflect residual antagonist actions at D2 (or D3) receptors. Selective blockade of D4 receptors was thus associated neither with a modification of dopaminergic transmission nor with antipsychotic (antiproductive) or extrapyramidal properties. The functional effects of selective D4 receptor blockade remain to be established.

0022-3565/98/2871-0167$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, D. Cussac, A. Gobert, F. Lejeune, J.-M. Rivet, C. M. La Cour, A. Newman-Tancredi, and J.-L. Peglion
S32504, a Novel Naphtoxazine Agonist at Dopamine D3/D2 Receptors: I. Cellular, Electrophysiological, and Neurochemical Profile in Comparison with Ropinirole
J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 903 - 920.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, B. Di Cara, M. Hill, M. Jackson, J. N. Joyce, J. Brotchie, S. McGuire, A. Crossman, L. Smith, P. Jenner, et al.
S32504, a Novel Naphtoxazine Agonist at Dopamine D3/D2 Receptors: II. Actions in Rodent, Primate, and Cellular Models of Antiparkinsonian Activity in Comparison to Ropinirole
J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 921 - 935.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, M. Brocco, M. Papp, F. Serres, C. D. La Rochelle, T. Sharp, J.-L. Peglion, and A. Dekeyne
S32504, a Novel Naphtoxazine Agonist at Dopamine D3/D2 Receptors: III. Actions in Models of Potential Antidepressive and Anxiolytic Activity in Comparison with Ropinirole
J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 936 - 950.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. B. Caine, S. S. Negus, N. K. Mello, S. Patel, L. Bristow, J. Kulagowski, D. Vallone, A. Saiardi, and E. Borrelli
Role of Dopamine D2-like Receptors in Cocaine Self-Administration: Studies with D2 Receptor Mutant Mice and Novel D2 Receptor Antagonists
J. Neurosci., April 1, 2002; 22(7): 2977 - 2988.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
E. Meririnne, A. Kankaanpaa, and T. Seppala
Rewarding Properties of Methylphenidate: Sensitization by Prior Exposure to the Drug and Effects of Dopamine D1- and D2-Receptor Antagonists
J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 539 - 550.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, A. Gobert, A. Newman-Tancredi, F. Lejeune, D. Cussac, J.-M. Rivet, V. Audinot, T. Dubuffet, and G. Lavielle
S33084, a Novel, Potent, Selective, and Competitive Antagonist at Dopamine D3-Receptors: I. Receptorial, Electrophysiological and Neurochemical Profile Compared with GR218,231 and L741,626
J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 1048 - 1062.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, A. Dekeyne, J.-M. Rivet, T. Dubuffet, G. Lavielle, and M. Brocco
S33084, a Novel, Potent, Selective, and Competitive Antagonist at Dopamine D3-Receptors: II. Functional and Behavioral Profile Compared with GR218,231 and L741,626
J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 1063 - 1073.
[Abstract] [Full Text]

Home page
 J PsychopharmacolHome page
M. J. Millan, F. Lejeune, and A. Gobert
Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents
J Psychopharmacol, March 1, 2000; 14(2): 114 - 138.
[Abstract] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, A. Gobert, K. Bervoets, J.-M. Rivet, S. Veiga, and M. Brocco
Induction of Spontaneous Tail-Flicks in Rats by Blockade of Transmission at N-Methyl-D-Aspartate Receptors: Roles of Multiple Monoaminergic Receptors in Relation to the Actions of Antipsychotic Agents
J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 672 - 683.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, A. Gobert, A. Newman-Tancredi, F. Lejeune, D. Cussac, J.-M. Rivet, V. Audinot, A. Adhumeau, M. Brocco, J.-P. Nicolas, et al.
S18327 (1-{2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin-2-one), a Novel, Potential Antipsychotic Displaying Marked Antagonist Properties at alpha 1- and alpha 2-Adrenergic Receptors: I. Receptorial, Neurochemical, and Electrophysiological Profile
J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 38 - 53.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, M. Brocco, J.-M. Rivet, V. Audinot, A. Newman-Tancredi, L. Maiofiss, S. Queriaux, N. Despaux, J.-L. Peglion, and A. Dekeyne
S18327 (1-{2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin-2-one), a Novel, Potential Antipsychotic Displaying Marked Antagonist Properties at alpha 1- and alpha 2-Adrenergic Receptors: II. Functional Profile and a Multiparametric Comparison with Haloperidol, Clozapine, and 11 Other Antipsychotic Agents
J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 54 - 66.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Millan, R. Schreiber, S. Monneyron, B. Denorme, C. Melon, S. Queriaux, and A. Dekeyne
S-16924, a Novel, Potential Antipsychotic with Marked Serotonin1A Agonist Properties. IV. A Drug Discrimination Comparison with Clozapine
J. Pharmacol. Exp. Ther., April 1, 1999; 289(1): 427 - 436.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.