SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug: Preclinical Research
Combined dopamine D 2 receptor antagonism and serotonin (5-HT) 1A receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-flu...
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| Veröffentlicht in: | Neuropsychopharmacology (New York, N.Y.) N.Y.), 2007-01, Vol.32 (1), p.78-94 |
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| creator | McCreary, Andrew C Glennon, Jeffrey C Ashby, Charles R Meltzer, Herbert Y Li, Zhu Reinders, Jan-Hendrik Hesselink, Mayke B Long, Stephen K Herremans, Arnoud H van Stuivenberg, Herman Feenstra, Rolf W Kruse, Chris G |
| description | Combined dopamine D
2
receptor antagonism and serotonin (5-HT)
1A
receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the
in vitro
and
in vivo
characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D
2/3
antagonist and 5-HT
1A
agonist. SLV313 possessed high affinity at human recombinant D
2
, D
3
, D
4
, 5-HT
2B
, and 5-HT
1A
receptors, moderate affinity at 5-HT
7
and weak affinity at 5-HT
2A
receptors, with little-no affinity at 5-HT
4
, 5-HT
6
,
α
1
, and
α
2
(rat), H
1
(guinea pig), M
1
, M
4
, 5-HT
3
receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT
1A
receptors (pEC
50
=9.0) and full antagonist activity at hD
2
(pA
2
=9.3) and hD
3
(pA
2
=8.9) receptors.
In vivo
, SLV313 antagonized apomorphine-induced climbing and induced 5-HT
1A
syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT
1A
antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT
1A
-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT
1A
receptor agonist and full D
2/3
receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia. |
| doi_str_mv | 10.1038/sj.npp.1301098 |
| format | Article |
| fullrecord | <record><control><sourceid>springer</sourceid><recordid>TN_cdi_springer_journals_10_1038_sj_npp_1301098</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1038_sj_npp_1301098</sourcerecordid><originalsourceid>FETCH-springer_journals_10_1038_sj_npp_13010983</originalsourceid><addsrcrecordid>eNqVkE1Lw0AURQdRsH5sXc-yBV8700na1F01li5UghYplBJCOjYT0nnDzFRM_6n_xkS6cOvqwT3nvsUl5IazPmciGriyr43pc8E4m0QnpMPHAYORCJanpMOiiQAuxPKcXDhXMsbD8SjqkO-3p3fBBe1y6A5vBcSqqDcW4V7qA674bbCOFX4pDSHUVQ8CoKsQugHMqj02WlJI3eZJbdWmsURj7aQv6moNiTLSZgelJX1Gjb9_86LCxpS9OzqlL_gpKxqjyXatFA_pq8yl8WjpVPtsi1o5TzO9oSHMF3z6Bx9Zgl5qr7KqLSjj6rxAr3Ia2_32ipx9ZJWT18d7SQazx8XDHJyxSm-lTUvcW92glLO0XTB1ZdosmB4XFP9v_ACW-Xsu</addsrcrecordid><sourcetype>Publisher</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug: Preclinical Research</title><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>McCreary, Andrew C ; Glennon, Jeffrey C ; Ashby, Charles R ; Meltzer, Herbert Y ; Li, Zhu ; Reinders, Jan-Hendrik ; Hesselink, Mayke B ; Long, Stephen K ; Herremans, Arnoud H ; van Stuivenberg, Herman ; Feenstra, Rolf W ; Kruse, Chris G</creator><creatorcontrib>McCreary, Andrew C ; Glennon, Jeffrey C ; Ashby, Charles R ; Meltzer, Herbert Y ; Li, Zhu ; Reinders, Jan-Hendrik ; Hesselink, Mayke B ; Long, Stephen K ; Herremans, Arnoud H ; van Stuivenberg, Herman ; Feenstra, Rolf W ; Kruse, Chris G</creatorcontrib><description>Combined dopamine D
2
receptor antagonism and serotonin (5-HT)
1A
receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the
in vitro
and
in vivo
characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D
2/3
antagonist and 5-HT
1A
agonist. SLV313 possessed high affinity at human recombinant D
2
, D
3
, D
4
, 5-HT
2B
, and 5-HT
1A
receptors, moderate affinity at 5-HT
7
and weak affinity at 5-HT
2A
receptors, with little-no affinity at 5-HT
4
, 5-HT
6
,
α
1
, and
α
2
(rat), H
1
(guinea pig), M
1
, M
4
, 5-HT
3
receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT
1A
receptors (pEC
50
=9.0) and full antagonist activity at hD
2
(pA
2
=9.3) and hD
3
(pA
2
=8.9) receptors.
In vivo
, SLV313 antagonized apomorphine-induced climbing and induced 5-HT
1A
syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT
1A
antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT
1A
-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT
1A
receptor agonist and full D
2/3
receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.</description><identifier>ISSN: 0893-133X</identifier><identifier>EISSN: 1740-634X</identifier><identifier>DOI: 10.1038/sj.npp.1301098</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Behavioral Sciences ; Biological Psychology ; Medicine ; Medicine & Public Health ; Neurosciences ; original-article ; Pharmacotherapy ; Psychiatry</subject><ispartof>Neuropsychopharmacology (New York, N.Y.), 2007-01, Vol.32 (1), p.78-94</ispartof><rights>American College of Neuropsychopharmacology 2007</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>McCreary, Andrew C</creatorcontrib><creatorcontrib>Glennon, Jeffrey C</creatorcontrib><creatorcontrib>Ashby, Charles R</creatorcontrib><creatorcontrib>Meltzer, Herbert Y</creatorcontrib><creatorcontrib>Li, Zhu</creatorcontrib><creatorcontrib>Reinders, Jan-Hendrik</creatorcontrib><creatorcontrib>Hesselink, Mayke B</creatorcontrib><creatorcontrib>Long, Stephen K</creatorcontrib><creatorcontrib>Herremans, Arnoud H</creatorcontrib><creatorcontrib>van Stuivenberg, Herman</creatorcontrib><creatorcontrib>Feenstra, Rolf W</creatorcontrib><creatorcontrib>Kruse, Chris G</creatorcontrib><title>SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug: Preclinical Research</title><title>Neuropsychopharmacology (New York, N.Y.)</title><addtitle>Neuropsychopharmacol</addtitle><description>Combined dopamine D
2
receptor antagonism and serotonin (5-HT)
1A
receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the
in vitro
and
in vivo
characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D
2/3
antagonist and 5-HT
1A
agonist. SLV313 possessed high affinity at human recombinant D
2
, D
3
, D
4
, 5-HT
2B
, and 5-HT
1A
receptors, moderate affinity at 5-HT
7
and weak affinity at 5-HT
2A
receptors, with little-no affinity at 5-HT
4
, 5-HT
6
,
α
1
, and
α
2
(rat), H
1
(guinea pig), M
1
, M
4
, 5-HT
3
receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT
1A
receptors (pEC
50
=9.0) and full antagonist activity at hD
2
(pA
2
=9.3) and hD
3
(pA
2
=8.9) receptors.
In vivo
, SLV313 antagonized apomorphine-induced climbing and induced 5-HT
1A
syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT
1A
antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT
1A
-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT
1A
receptor agonist and full D
2/3
receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.</description><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Neurosciences</subject><subject>original-article</subject><subject>Pharmacotherapy</subject><subject>Psychiatry</subject><issn>0893-133X</issn><issn>1740-634X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqVkE1Lw0AURQdRsH5sXc-yBV8700na1F01li5UghYplBJCOjYT0nnDzFRM_6n_xkS6cOvqwT3nvsUl5IazPmciGriyr43pc8E4m0QnpMPHAYORCJanpMOiiQAuxPKcXDhXMsbD8SjqkO-3p3fBBe1y6A5vBcSqqDcW4V7qA674bbCOFX4pDSHUVQ8CoKsQugHMqj02WlJI3eZJbdWmsURj7aQv6moNiTLSZgelJX1Gjb9_86LCxpS9OzqlL_gpKxqjyXatFA_pq8yl8WjpVPtsi1o5TzO9oSHMF3z6Bx9Zgl5qr7KqLSjj6rxAr3Ia2_32ipx9ZJWT18d7SQazx8XDHJyxSm-lTUvcW92glLO0XTB1ZdosmB4XFP9v_ACW-Xsu</recordid><startdate>20070101</startdate><enddate>20070101</enddate><creator>McCreary, Andrew C</creator><creator>Glennon, Jeffrey C</creator><creator>Ashby, Charles R</creator><creator>Meltzer, Herbert Y</creator><creator>Li, Zhu</creator><creator>Reinders, Jan-Hendrik</creator><creator>Hesselink, Mayke B</creator><creator>Long, Stephen K</creator><creator>Herremans, Arnoud H</creator><creator>van Stuivenberg, Herman</creator><creator>Feenstra, Rolf W</creator><creator>Kruse, Chris G</creator><general>Springer International Publishing</general><scope/></search><sort><creationdate>20070101</creationdate><title>SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug</title><author>McCreary, Andrew C ; Glennon, Jeffrey C ; Ashby, Charles R ; Meltzer, Herbert Y ; Li, Zhu ; Reinders, Jan-Hendrik ; Hesselink, Mayke B ; Long, Stephen K ; Herremans, Arnoud H ; van Stuivenberg, Herman ; Feenstra, Rolf W ; Kruse, Chris G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-springer_journals_10_1038_sj_npp_13010983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Behavioral Sciences</topic><topic>Biological Psychology</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Neurosciences</topic><topic>original-article</topic><topic>Pharmacotherapy</topic><topic>Psychiatry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McCreary, Andrew C</creatorcontrib><creatorcontrib>Glennon, Jeffrey C</creatorcontrib><creatorcontrib>Ashby, Charles R</creatorcontrib><creatorcontrib>Meltzer, Herbert Y</creatorcontrib><creatorcontrib>Li, Zhu</creatorcontrib><creatorcontrib>Reinders, Jan-Hendrik</creatorcontrib><creatorcontrib>Hesselink, Mayke B</creatorcontrib><creatorcontrib>Long, Stephen K</creatorcontrib><creatorcontrib>Herremans, Arnoud H</creatorcontrib><creatorcontrib>van Stuivenberg, Herman</creatorcontrib><creatorcontrib>Feenstra, Rolf W</creatorcontrib><creatorcontrib>Kruse, Chris G</creatorcontrib><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McCreary, Andrew C</au><au>Glennon, Jeffrey C</au><au>Ashby, Charles R</au><au>Meltzer, Herbert Y</au><au>Li, Zhu</au><au>Reinders, Jan-Hendrik</au><au>Hesselink, Mayke B</au><au>Long, Stephen K</au><au>Herremans, Arnoud H</au><au>van Stuivenberg, Herman</au><au>Feenstra, Rolf W</au><au>Kruse, Chris G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug: Preclinical Research</atitle><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle><stitle>Neuropsychopharmacol</stitle><date>2007-01-01</date><risdate>2007</risdate><volume>32</volume><issue>1</issue><spage>78</spage><epage>94</epage><pages>78-94</pages><issn>0893-133X</issn><eissn>1740-634X</eissn><abstract>Combined dopamine D
2
receptor antagonism and serotonin (5-HT)
1A
receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the
in vitro
and
in vivo
characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D
2/3
antagonist and 5-HT
1A
agonist. SLV313 possessed high affinity at human recombinant D
2
, D
3
, D
4
, 5-HT
2B
, and 5-HT
1A
receptors, moderate affinity at 5-HT
7
and weak affinity at 5-HT
2A
receptors, with little-no affinity at 5-HT
4
, 5-HT
6
,
α
1
, and
α
2
(rat), H
1
(guinea pig), M
1
, M
4
, 5-HT
3
receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT
1A
receptors (pEC
50
=9.0) and full antagonist activity at hD
2
(pA
2
=9.3) and hD
3
(pA
2
=8.9) receptors.
In vivo
, SLV313 antagonized apomorphine-induced climbing and induced 5-HT
1A
syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT
1A
antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT
1A
-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT
1A
receptor agonist and full D
2/3
receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><doi>10.1038/sj.npp.1301098</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0893-133X |
| ispartof | Neuropsychopharmacology (New York, N.Y.), 2007-01, Vol.32 (1), p.78-94 |
| issn | 0893-133X 1740-634X |
| language | eng |
| recordid | cdi_springer_journals_10_1038_sj_npp_1301098 |
| source | EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Behavioral Sciences Biological Psychology Medicine Medicine & Public Health Neurosciences original-article Pharmacotherapy Psychiatry |
| title | SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug: Preclinical Research |
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