The dual-acting AChE inhibitor and H₃ receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats

Both the acetylcholine esterase (AChE) and the histamine H₃ receptor (H₃R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H₃R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H₃R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC₅₀ of 5.4 μM on hAChE and hH₃R antagonism with K_i of 2.54 μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5 mg/kg, i.p.) on memory deficits induced by the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2 mg/kg, i.p.) and DIZ (0.1 mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25 mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H₂R antagonist zolantidine (ZOL, 10 mg/kg, i.p.), but not with the CNS penetrant H₁R antagonist pyrilamine (PYR, 10 mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25 mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10 mg/kg, i.p.) and SCO (1.0 mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, observed through histaminergic H₂R as well as muscarinic cholinergic neurotransmission. These results demonstrate the ameliorative effects of UW-MD-72 in two in-vivo memory models and provide evidence for the potential of dual-acting AChEI and H₃R antagonists to treat cognitive disorders.