The Discovery And Study Of Novel Potential Multireceptor Antipsychotic Candidate Drug

Schizophrenia is the most severe and harmful mental disorder which has been referred to as the“cancer”of psychiosis.Regarded as a spectrum disorder,schizophrenia is categorized by positive,negative,and cognitive symptoms.Improving the symptomatic treatment of schizophrenia by typical and atypical antipsychotics remains the important goal for several decades.In addition,inadequacies in treating cognitive impairments create an unmet clinical need for patients suffering from schizophrenia.Drugs that have multiple targets are generally accepted to be better antipsychotic agents.Simultaneous action on both dopamine receptors and serotonin receptors have become the mainstream of discovering novel multireceptor antipsychotics.In this study,the design,synthesis and pharmacological characterization of several series of compounds targeting D₂,D₃,5-HT_1A and 5-HT_2A receptors along with selectivity for D₃ versus D₂ subtype were described.The main research contents and results are as follows:1.The design and in vitro study of new compoundsA total of ninety compounds were designed and classified as eight serials?A-H?.The binding profiles of class A compounds were nanomolar or subnanomolar affinities for D₂,D₃,5-HT_1A,and 5-HT_2A receptors.The selected compounds also displayed a 10 to 30-fold selectivity for the D₃ versus D₂ subtype,together with a higher receptor affinity for 5-HT_2A than D₂?K_i ratio 1.3-12.6?.Similar binding characters were detected for class B and class D compounds.Class C,E,F,G and H compounds did not possess the multireceptor affinity profiles.A detailed structure-activity relationship investigation of class A derivatives revealed that multiple factors,such as substituents on the amide,the configuration of the spacer,and substitutions at the 6-position of benzo[d]isothiazole,had influence on the affinity for the D₂,D₃,5-HT_1A and 5-HT_2A receptors both individually and collectively.2.The pharmacological evaluation and comparison of selected class A compoundsCompounds SIPI6398,SIPI6414,SIPI6427 and SIPI6441 were selected as potential atypical antipsychotic agents and evaluated in further studies due to their prominent effect on serotonergic and dopaminergic receptors.The data indicated that SIPI6398 had D₂,D₃,5-HT_1A and 5-HT_2A antagonism as well as high selectivity for the affinity profile compared to side effect target binding.SIPI6398 exhibited a good safety profile in subacute toxicity test,Ames test and xCELLigence RTCA Cardio test.In vivo animal model tests displayed that 9j was a promising multireceptor antipsychotic with noticeable cognitive deficit improvement.SIPI6398 displayed low potential for catalepsy,consistent with risperidone.The incidence of sedation of SIPI6398 was lower than cariprazine.In addition,favorable brain penetration of SIPI6398 in rats was observed.3.The discovery of candidates of SIPI6398Compounds SIPI6437,SIPI7685,SIPI7686 and SIPI7693 in class B and SIPI7710 in class D showed similar affinity characters compared with SIPI6398,and selected for further studies.Among these derivatives,SIPI7686 and SIPI7710 showed good ADME properties in vitro metabolic stability assays and low affinity for hERG channels.Besides,SIPI7710 exhibited good pharmacokinetic parameters in rats.4.ChemistryClass A compounds and cariprazine were synthesized via the facile construction of 2-??trans?-4-acetamidocyclohexyl?acetic acid.A single X-ray crystal structure was obtained for cariprazine,demonstrating that the cyclohexane ring was in the trans conformation.It is worth noting that the corresponding compounds of class A were preferentially in the trans conformation of cyclohexane ring.Compounds of class B and class C were achieved through a similar process in preparation of class A.Several other new routes were designed and applied to obtain class D,E,F,G and H compounds respectively.Furthermore,SIPI6398 was prepared on hectogram-scale via the optimized route to class A compounds of in over 99.8%HPLC purity.Taken together,our present work has demonstrated that SIPI6398 was a promising multireceptor atypical antipsychotic.This study sheds light on the development of novel potential multitarget atypical antipsychotics for the treatment of schizophrenia.