SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4- [5-(4-fluoro-phenyl)- pyridin-3-ylmethyl]-piperazine monohydrochloride): A novel dopamine D 2 receptor antagonist and 5-HT1A receptor agonist potential antipsychotic drug

Andrew C. McCreary*, Jeffrey C. Glennon, Charles R. Ashby, Herbert Y. Meltzer, Zhu Li, Jan Hendrik Reinders, Mayke B. Hesselink, Stephen K. Long, Arnoud H. Herremans, Herman Van Stuivenberg, Rolf W. Feenstra, Chris G. Kruse

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Combined dopamine D2 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 D2/3 antagonist and 5-HT1A agonist. SLV313 possessed high affinity at human recombinant D2, D3, D4, 5-HT2B, and 5-HT1A receptors, moderate affinity at 5-HT7 and weak affinity at 5-HT 2A receptors, with little-no affinity at 5-HT4, 5-HT 6, α1, and α2 (rat), H1 (guinea pig), M1, M4, 5-HT3 receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT1A receptors (pEC50=9.0) and full antagonist activity at hD2 (pA2=9.3) and hD3 (pA2=8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT1A syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT1A 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-HT1A-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-HT1A receptor agonist and full D2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.

Original languageEnglish (US)
Pages (from-to)78-94
Number of pages17
JournalNeuropsychopharmacology
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • 5-HT
  • Atypical antipsychotic
  • D
  • Medial prefrontal cortex
  • Neuroleptic
  • SLV313

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4- [5-(4-fluoro-phenyl)- pyridin-3-ylmethyl]-piperazine monohydrochloride): A novel dopamine D <sub>2</sub> receptor antagonist and 5-HT<sub>1A</sub> receptor agonist potential antipsychotic drug'. Together they form a unique fingerprint.

Cite this