α7 receptor agonists(Qingdao University)

Alzheimer's disease (AD) is the leading cause of dementia worldwide, but current therapies provide only symptomatic relief. Multi-target directed ligands (MTDLs) represent a promising approach to address AD pathology by modulating multiple targets with a single molecule. Here we describe quinuclidine carbamates that act simultaneously on butyrylcholinesterase (BChE) and the cholinergic α7 nicotinic receptor (α7 nAChR), thereby approaching cholinergic dysfunction at two levels: by modulating acetylcholine degradation and by direct agonism at this receptor. Starting with the α7 nAChR agonist bradanicline, its amide group was replaced by a carbamate moiety to enhance BChE inhibition while retaining receptor agonism. These quinuclidine carbamates inhibited BChE in the submicromolar range with the desired selectivity over acetylcholinesterase (AChE). In a calcium-flux assay on recombinant HEK293T cells expressing the α7 nAChR, all compounds were agonists of the α7 nAChR in the nanomolar range. Importantly, compound 6b displayed balanced, submicromolar activity against both targets. The crystal structures confirmed non-covalent binding to the active site of human BChE, and the 6b-hBChE complex also revealed an unprecedented flip of Tyr440, representing the first described example of backdoor opening for hBChE. Taken together, these results demonstrate that quinuclidine carbamates are promising dual modulators of hBChE and α7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery.

We investigated effects of long-term and acute administration of EQU-001 (ivermectin) against NMDA-triggered spasms in immature rats prenatally exposed to betamethasone and in the model of infantile epilepsy spasms syndrome (IESS). Pregnant rats were injected with betamethasone on gestational day 15 (2 ×0.4 mg/kg, i.p.). Offspring were injected with ivermectin once daily (1-4 mg/kg, i.p.) from postnatal day (P) 10 through P15. Spasms were triggered on P15 with NMDA (17 mg/kg, i.p.). Other rats received a single dose of ivermectin (1-8 mg/kg, i.p.) on P15 prior to NMDA to test acute anticonvulsant activity. Also, a randomized model was used: The spasms were triggered on P12 and ivermectin treatment (4 mg/kg) was initiated after this bout of spasms on P12, P13 and P14, with additional spasms elicited on P13 and P15. A nicotinic cholinergic α7 agonist was used to mimic effects of ivermectin, and α7 antagonist was used together with ivermectin to prevent its effects. P10-P15 administration of 4 mg/kg of ivermectin significantly suppressed occurrence of spasms on P15, an effect comparable to that of ACTH (positive control). Conversely, an acute P15 administration of ivermectin had no effects on spasms. Ivermectin in the randomized trial suppressed occurrence of spasms as well P15/P12 ratio of spasms. Ivermectin also decreased body weight gain in those animals. None of the nicotinic cholinergic α7 drugs mimicked or prevented effects of ivermectin. Our data indicate that ivermectin may become a powerful tool in the armamentarium for treatment of IESS, however the mechanisms of this action remain to be determined.