Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound

Impact of Community Popular Opinion Leader Intervention on Ocular Epidemic Study / 中国医科大学学报

Objective To observe the role of community popular opinion leader (POL) intervention on ocular epidemic study. Methods During the process of epidemiological survey of eye disease in Shenyang City,the community POL was interviewed to observe the change of the follow-up population from 2015 to 2016 and the effects of the POL intervention were analyzed. Results The study population follow-up rate was significantly improved after POL intervention (χ2 = 85.42,P < 0.01),the male-to-female ratio was balanced (χ2 = 6.51, P = 0.01),and more participants were willing and hoped to participate in the epidemic study for a long time. Conclusion Community POLs can improve the follow-up rate of epidemiological surveys and mobilize the enthusiasm of the population to participate in epidemiological investigations.

Synthesis and analgesic activities of phenyl piperazinyl aralkyl ketone derivatives / 药学学报

To explore novel non-opioid analgesic agents, 16 compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. YX0611-1 was treated as the leading compound. The results of mice writhing model and hot plate model showed that compounds 2, 7, 8, 9, 11 and 15 had obvious analgesic activities in vivo. The test of affinity to mu, delta, kappa receptor displayed that active compounds didn't act on opioid receptor. The results of preliminary toxicity and pharmacokinetic tests showed that compound 7 had better safety and pharmacokinetic properties than that of YX0611-1, and it deserved further development.