E-5842: A new potent and preferential sigma ligand. Preclinical pharmacological profile

Abstract

E-5842 is a new sigma-receptor ligand. Its preclinical pharmacological profile suggests that E-5842 may behave as an atypical antipsychotic, with low tendency to cause EPS and efficacy against the positive as well as the negative symptoms of schizophrenia. 1. E-5842 displays high affinity for the sigma(l) receptor and low to moderate affinity (one to two orders of magnitude) for other receptors (α(2B), α(1A), α(1B))- Its low affinity for the dopamine D2 receptor indicates low propensity to cause EPS. 2. In a series of tests predicting antipsychotic efficacy, E-5842 inhibited apomorphine-induced climbing and mescaline-induced scratching in mice. Both tests, together with the inhibition of the CAR, the inhibition of the hyperactivity induced by d-amphetamine, and the blockade of apomorphine- induced disruption of PPI, clearly show that E-5842 behaves as an antipsychotic drug affecting the dopamine system and more specifically the mesolimbic pathway. 3. E-5842 displays a profile of a compound with low EPS liability. At very high doses, the compound does not induce any catalepsy in rodents. E-5842 attenuates the agitation induced by apomorphine in rats at a given dose, but more than twice this dose is needed to attenuate the stereotyped behavior induced by apomorphine. These results clearly indicate the preferential blockade by E-5842 of behavior associated with the activation of the mesolimbic/mesocortical dopaminergic system. Indeed, and related to the low EPS liability, no upregulation of D2 receptors or dopamine D2-receptor hypersensitization was observed after chronic treatment with E-5842. Taken together, these results suggest that E-5842 does not directly interact with dopamine receptors and that its pattern of activity is quite similar to that of clozapine and other atypical antipsychotics, suggesting low propensity to induce EPS. 4. The rat social interaction paradigm has been used as a preclinical correlate of some of the negative symptoms observed in schizophrenic patients. E-5842 shows activity in this test. E-5842 has a clear anxiolytic potential as it increases the social interaction in rats and is effective in the black-and-white box test, increasing the time spent by mice in the white section of the box. The results obtained in both paradigms (increased social interaction and anxiolytic activity), suggest that E-5842 should reduce some aspects of the negative symptoms, given the similarity of our results with those clozapine and other atypical antipsychotics. 5. E-5842 has a unique neurochemical profile. Acute administration of the compound elicits a huge increase in the extracellular levels of dopamine in the medial prefrontal cortex. Similarly, acute administration of E-5842 induces a significant increase in the levels of c-Fos protein in the same brain area. These results clearly correlate with the results observed with clozapine and are completely different to those observed with haloperidol and other classical antipsychotics. These results could indicate some degree of efficacy, since it has been suggested that not only negative symptoms but also cognition symptoms may be associated with decreased cortical dopaminergic activity. 6. All together, our results suggest that E-5842 is a quite selective sigma(l) ligand, although interactions with other receptors cannot be completely excluded, especially depending on the administered dose level. From preliminary pharmacokinetic studies (Esteve S. A, data on file), it is known that substantial plasma levels of E-5842 are achieved after oral administration of different doses of the product. It is also known that the levels of compound can be higher in brain in plasma 1 to 3 h after administration, but the exact concentration of unaltered compound in the whole brain or in specific regions of rat brain is not known. In many case, is most of the tests used to assess its antipsychotic activity the effective dose of E-5842 is in a low enough range to suggest that this activity is mainly due to the interaction with the sigma receptor.