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), alpha(1), and alpha(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.