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

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-dihydrobenzo[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 , a 1 , and a 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 ¼ 9.0) and full antagonist activity at hD 2 (pA 2 ¼ 9.3) and hD 3 (pA 2 ¼ 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. Neuropsychopharmacology (2007) 32, 78-94.

Synthesis and dual D2and 5-HT1Areceptor binding affinities of 5-piperidinyl and 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones

“…Reaction of 16 with CDI in THF, heating the mixture at 80 C for 6 h, finally gave access to the key intermediate 17 in an overall yield of 42% from 14. Alternatively, intermediate 17 was also synthesized from 14 by hydrogenation of 14 over Pd-C at 10 psi to produce diamine (18), which was treated with CDI in THF to generate intermediate 13.…”

“…Indeed, numerous mechanistic considerations [12][13][14] and preclinical evidences [15][16][17] support the potential of such a combination. Consequently, adoprazine (3) (SLV-313) and bifeprunox (4), bearing potent D 2 receptor antagonist and 5-HT 1A receptor agonist properties, were developed 18 ( Figure 1). Although compound 4 completed phase III clinical trials, its antipsychotic efficacy was determined to be inferior to that of risperidone and olanzapine 9 and, despite a satisfactory tolerance profile, the US Food and Drug Administration (FDA) did not grant marketing approval.…”

New Arylpiperazinylalkyl Derivatives of 8‐Alkoxy‐purine‐2,6‐dione and Dihydro[1,3]oxazolo[2,3‐f]purinedione Targeting the Serotonin 5‐HT1A/5‐HT2A/5‐HT7 and Dopamine D2 Receptors

“…The structure-activity relationships in the group of 1-aryl-4-(phenylarylmethyl)piperazines [7] led to obtaining SLV 313 (adoprazine) (Fig. 1) [8]. The multireceptor strategy has also been explored in a series of isoquinoline-and quinolineamide-and sulfonamide-derivatives of long chain arylpiperazines (LCAPs) exemplified by structures A and B ( Fig.…”

Induction by Antipsychotics of “Win-Shift” in the Drug Discrimination Paradigm

“…The experiments determined the dose-dependent effects of haloperidol and of other clinically established antipsychotics (i.e., chlorpromazine, thioridazine, raclopride, aripiprazole, nemonapride, ziprasidone, olanzapine, clozapine, and risperidone) as well as those of further agents currently being developed for the treatment of schizophrenia [i.e., F 15063 (Depoortère et al, 2007), jpet.aspetjournals.org bifeprunox, SLV313 (McCreary et al, 2007), and SSR181507 (Claustre et al, 2003)]. Also tested were compounds that may interfere with DD performance by different molecular and/or neurobiological mechanisms (see Discussion; e.g., scopolamine and dizocilpine) or that constitute useful tools in examining the possible involvement of some major neurotransmitter systems (e.g., ritanserin, naltrexone, and prazosin).…”