Odapipam

Butyrylcholinesterase (BChE) is a nonspecific cholinesterase enzyme that hydrolyzes choline-based esters. BChE plays a critical role in maintaining normal cholinergic function like acetylcholinesterase (AChE) through hydrolyzing acetylcholine (ACh). Selective BChE inhibition has been regarded as a viable therapeutic approach in Alzheimer's disease. As of now, a limited number of selective BChE inhibitors are available. To identify BChE inhibitors rapidly and efficiently, we have screened 8998 compounds from several annotated libraries against an enzyme-based BChE inhibition assay in a quantitative high-throughput screening (qHTS) format. From the primary screening, we identified a group of 125 compounds that were further confirmed to inhibit BChE activity, including previously reported BChE inhibitors (e.g., bambuterol and rivastigmine) and potential novel BChE inhibitors (e.g., pancuronium bromide and NNC 756), representing diverse structural classes. These BChE inhibitors were also tested for their selectivity by comparing their IC₅₀ values in BChE and AChE inhibition assays. The binding modes of these compounds were further studied using molecular docking analyses to identify the differences between the interactions of these BChE inhibitors within the active sites of AChE and BChE. Our qHTS approach allowed us to establish a robust and reliable process to screen large compound collections for potential BChE inhibitors.

To determine whether specific dopamine receptor antagonists block alfentanil-induced locomotor stimulation in horses.

Randomized, prospective, crossover experiment.

Eight adult horses (462-604 kg).

Doses of dopamine-1 (D1) (NNC 01-0756) and dopamine-2 (D2) antagonists (eticlopride) were selected in a pilot study prior to a three part, blinded, cross-over study. In part 1, horses received 7.5 micro g kg-1 eticlopride, 5 micro g kg-1 NNC 01-0756 or an equal volume of saline. In part 2, they received both antagonists and in part 3, acepromazine at 0.05 mg kg-1. Locomotor activity was assessed by counting the steps taken by a marked forefoot per 2 minutes. The D antagonist was injected IV after a 20-minute control period. The horses were observed for 10 minutes before alfentanil (20 micro g kg-1) was injected IV. Locomotor activity was then monitored for 60 minutes. Statistical analysis was performed on step counts following alfentanil normalised by subtracting the mean control step count from each value recorded after alfentanil. Data were analysed using Friedman tests and Tukey-Kramer comparisons.

Alfentanil increased locomotor activity for 10 minutes. NNC 01-0756 tended to reduce locomotor activity between 0 and 10 minutes (p = 0.261), but neither D antagonist suppressed it significantly. The combination of D antagonists induced more step counts than saline or acepromazine (p = 0.0265) in the 20-40-minute period and more than saline, acepromazine or eticlopride between 40 and 60 minutes (p = 0.0003).

Neither D1 nor D2 antagonists inhibited alfentanil-induced locomotor activity. Both drugs appeared to cause locomotor stimulation of their own.

D1 and D2 antagonism did not reduce opioid-induced excitement in horses and is not suitable for reducing the incidence of this unwanted side-effect of opioids.