Towards a New Generation of Potential Antipsychotic Agents Combining D₂ and 5-HT_1A Receptor Activities

Abstract

We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist properties in the same molecule. We describe the structure-activity relationship that lead us to the promising derivative: N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine 16. The latter has high affinity for D2 and 5-HT1A receptors, whereas it possesses only a weak affinity for 5-HT2A sites. In cellular models of signal transduction, 16 behaves as a silent antagonist at rD2 receptors while activating h5-HT1A receptors with an efficacy at least equivalent to that of the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. These dual actions confer a unique pharmacological profile to the product. In a behavioral model predictive of positive symptoms, 16 has an activity comparable to that of the typical antipsychotic haloperidol, while it is devoid of cataleptogenic effects. Although it produces behaviors characteristic of 5-HT1A receptor activation in rats, these occur at doses 100 times higher than those with (+/-)-8-OH-DPAT. We believe that the relative balance of D2 and 5-HT1A actions in 16 is appropriate, possibly optimal, to ensure superior efficacy and tolerability over existing antipychotic drugs.

Synthesis of New 4-Aryl-1-(biarylmethylene)piperidines. Structural Analogs of Adoprazine (SLV313)

“…The known aldehydes 6e and 6f were synthesized from their corresponding bromides 8 and 9 by employing literature-known procedures [11] (Scheme 1).…”

“…However, the failure of 1 and 2 to oppose phencyclidine-induced social interaction deficits suggested that an appropriate 'balance' of activity at these sites is necessary for activity in this model [4]. Thus, the need to discover compounds having varying ratios of D 2 and 5-HT 1A activities continued [6]. This report describes the synthesis of a series of new 4-aryl-1-(biarylmethylene)piperidines 3a -f, 4a -f and 5a -f, structurally related to 1 (Fig.…”

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

“…In addition, the failure of 3 and 4 to oppose phencyclidineinduced social interaction deficits suggested that an appropriate ''balance'' of activity at these sites is necessary for activity in this model 19 . Thus, the need to discover compounds having varying ratios of D 2 and 5-HT 1A activities continued 20 .…”

“…The mixture was diluted with ethyl acetate (25 mL) and washed successively with water (15 mL), brine (15 mL), dried over Na 2 SO 4 and evaporated. Column chromatography on silica gel, eluting with ethyl acetate:hexanes (10:90) and then the ratio was changed to 20 43 mmol), toluene (8 mL) and compound 7 (3.68 g, 14.26 mmol) were added. While stirring the reaction mixture at room temperature, the air in the flask was removed and replaced by N 2 .…”

Synthesis of New 1-Aryl-4-(biarylmethylene)piperazine Ligands, Structurally Related to Adoprazine (SLV313)

“…However, 1 and 2 failed to oppose phencyclidine-induced social interaction deficits, suggesting that an appropriate 'balance' of activity at these sites is necessary for activity in this model [4]. There is a growing need to develop comc 2012 Verlag der Zeitschrift für Naturforschung, Tübingen · http://znaturforsch.com pounds having varying ratios of D 2 and 5-HT 1A activities [6]. This report describes the synthesis of a series of new 1-aryl-4-(biarylmethylene)piperazines 3a -3f, 4a -4f and 5a -5f, structurally related to 1 (Fig.…”