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In vitro characterization of SLV308 (7‐[4‐methyl‐1‐piperazinyl]‐2(3H)‐benzoxazolone, monohydrochloride): A novel partial dopamine D 2 and D 3 receptor agonist and serotonin 5‐HT 1A receptor agonist
Author(s) -
Glen Jeffrey C.,
Van Scharrenburg Guus,
Ronken Eric,
Hesselink Mayke B.,
Reinders JanHendrik,
Van Der Neut Martina,
Long Stephen K.,
Feenstra Rolf W.,
McCreary Andrew C.
Publication year - 2006
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20330
Subject(s) - endogenous agonist , agonist , partial agonist , chemistry , receptor , gtpgammas , dopamine receptor d3 , dopamine , dopamine receptor d2 , pharmacology , d2 like receptor , endocrinology , dopamine receptor d1 , intrinsic activity , medicine , dopamine receptor , 5 ht receptor , serotonin , biology , biochemistry
Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7‐[4‐methyl‐1‐piperazinyl]‐2( 3H )‐benzoxazolonemonohydrochloride). SLV308 binds to dopamine D 2 , D 3 , and D 4 receptors and 5‐HT 1 A receptors and is a partial agonist at dopamine D 2 and D 3 receptors and a full agonist at serotonin 5‐HT 1 A receptors. At cloned human dopamine D 2,L receptors, SLV308 acted as a potent but partial D 2 receptor agonist (pEC 50 = 8.0 and pA 2 = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D 3 receptors, SLV308 acted as a partial agonist in the induction of [ 35 S]GTPγS binding (intrinsic activity of 67%; pEC 50 = 9.2) and antagonized the dopamine induction of [ 35 S]GTPγS binding (pA 2 = 9.0). SLV308 acted as a full 5‐HT 1 A receptor agonist on forskolin induced cAMP accumulation at cloned human 5‐HT 1 A receptors but with low potency (pEC 50 = 6.3). In rat striatal slices SLV308 concentration‐dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D 2 and D 3 receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K + ‐stimulated [ 3 H]‐dopamine release from rat striatal slices (pA 2 = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA 2 = 8.5), but the partial D 2 agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D 2 and D 3 receptors with full efficacy low potency serotonin 5‐HT 1 A receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease. Synapse 60:599–608, 2006. © 2006 Wiley‐Liss, Inc.