ABSTRACT
Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel critical for cognition, learning and memory. Deficiency of neuronal α7 nAChR has been implicated in the cognitive deficits and neuropsychiatric disorders. Chemical activation of α7 nAChR improves neurological functions in animal models. In this study, we designed and synthesized a series of indolizine derivatives with various substitutions at different positions on the scaffold, and investigated their structure-activity relationships (SAR). All compounds were screened and evaluated for their agonist activity using the two-electrode voltage clamp recording system in Xenopus oocytes expressing human α7 nAChR. Compound 16c carrying 6-methylindolizine moiety activates α7 nAChR with EC50 at 1.60±0.19 μmol·L-1 and maximum effect (Emax) of 69.0%±2.8% compared with 3 mmol·L-1 ACh. Compound 17b with 8-cyclopropyl substitution shows an increased Emax of 81.1%±9.3% with EC50 at 2.74±0.74 μmol·L-1. The SAR of the series shows that introducing the small hydrophobic groups at 6- or 8- position can improve both potency and maximum effect.
ABSTRACT
Objective To investigate the effect of mind-regulating and collateral-unblocking acupuncture on carotid hemodynamics in leukoaraiosis patients. Methods Sixty leukoaraiosis patients were treated with mind-regulating and collateral-unblocking acupuncture. The Mini Mental Sate Examination (MMSE) score and the Montreal Cognitive Assessment (MoCA) score were recorded in the patients before and after treatment. Pre-and post-treatment carotid hemodynamic indices were compared. Results There were statistically significant pre-/post-treatment differences in the MMSE score and the MoCA score (P<0.01) and in common carotid, internal carotid and vertebral artery hemodynamic indices (peak systolic blood flow velocity, end-dystolic flow velocity, vascular resistance index and vascular pulsation index) (P<0.05) in the patients. Conclusions Mind-regulating and collateral-unblocking acupuncture can improve cognitive disorder in leukoaraiosis patients. Meanwhile, it has a marked improving effect on carotid hemodynamics in the patients.