1. ¹Solvay Pharmaceuticals Research, Weesp, The Netherlands
2. ²Pharmaceutical Sciences Department, St John's University, Jamaica, Queens, NY, USA
3. ³Psychopharmacology Division, Psychiatry Department, Vanderbilt University School of Medicine, Nashville, TN, USA

Correspondence: Dr AC McCreary, Solvay Pharmaceuticals Research, CJ van Houtenlaan 36, 1381 CP, Weesp, The Netherlands. Tel: +31 2944 79514; E-mail: andrew.mccreary@solvay.com

Received 1 August 2005; Accepted 13 March 2006; Published online 17 May 2006.

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 D_2/3 antagonist and 5-HT_1A agonist. SLV313 possessed high affinity at human recombinant D₂, D₃, D₄, 5-HT_2B, and 5-HT_1A receptors, moderate affinity at 5-HT₇ and weak affinity at 5-HT_2A receptors, with little-no affinity at 5-HT₄, 5-HT₆, ₁, and ₂ (rat), H₁ (guinea pig), M₁, M₄, 5-HT₃ receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT_1A 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-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.