Molecular Combination of the Dopamine and Serotonin Scaffolds Yield in Novel Antipsychotic Drug Candidates - Characterization by in vivo Experiments

Abstract

Serotonin and dopamine play an important role in the aetiology of schizophrenia. Combination of the structural scaffolds of both neurotransmitters in a single molecule lead to aromatic [d,g]-bisannelated azecine derivatives, which have been shown to be nanomolar to subnanomolar dopamine D1-D5 receptor antagonists with a preference for the D1 family. In this work the potential antipsychotic activity of some azecine derivatives was predicted by their dopamine receptor affinities obtained in vitro from radioligand binding experiments and conclusively confirmed in vivo (rats) by applying a conditioned avoidance model. Furthermore, the compounds were tested in vivo for the development of catalepsy, which is a predictive parameter for extra-pyramidal side-effects caused by many antipsychotics. The investigated azecines displayed low cytotoxicity, and the affinities for human dopamine D1-D5 and serotonin 5-HT2 A receptors were in a nanomolar range. In vivo, their antipsychotic activities in the rat model were comparable with those of haloperidol and risperidone, but revealed a 2-5 times better therapeutic range with regard to catalepsy. Preliminary tests for oral bioavailability also revealed promising results for this new class of potential antipsychotic compounds. In conclusion, our in vivo experiments show that aromatic [d,g]-annelated azecines represent a novel and advantageous class of potential atypical neuroleptics.

A Novel Non‐phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors

“…Due to their phenolic nature, these compounds are predisposed to poor pharmacokinetics (low bioavailability), which would restrict their utility for in vivo experiments and render them unsuitable for clinical development. Accordingly, our preliminary in vivo evaluations have shown that compound 1 (LE404) has a low oral bioavailability when administered to rats [6]. Studies on other classes of phenolic dopamine antagonists, in particular SCH23390 and SCH39166, have led to similar results [7] [8].…”

Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics

“…Thus, azecines are a novel class of antidopaminergic drug candidates with preferential binding to the D 1 receptor subtype (D 1 ,D 5 ) [5]. Moreover, tests have shown that they bind as antagonists at the 5-HT 2A receptor [11]. Up to now no D 5selective drugs are available and the function of the D 5 -receptor is not yet understood exactly [1].…”

“…For receptor functionality, the substitution pattern is fundamental [11]. Various derivatives (▶Fig.…”

“…After 240 min throughout the test (jumps [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], no significant (p ≤ 0.05) difference was visible between reaction times of the con-trol group and the treatment group. After 60 and 150 min, all reaction times of jumps 6-15 are significantly different from the control value.…”

Current and future treatment modalities in schizophrenia: novel antipsychotic drugs and cognitive therapy

“…Even so, it may be possible to design new drugs with combinations of affinities that avoid those known to be associated with side-effects. For instance, the combination of the 'structural scaffolds' of dopamine and serotonin has produced a group of azecine derivatives, which are effective in animal models of psychosis but manifest substantially better tolerability than both haloperidol and risperidone [20].…”