Behavioural pharmacologyUsing cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication

Benzylquinolone carboxylic acid (BQCA) is a recently described cholinergic muscarinic M1 receptor positive allosteric modulator having potential as cognitive enhancer in dementia. The present study focused on the characterisation of BQCA's mode of action in relation to positive effects on memory and side-effects in an animal model. To get insight into this mode of action, in vitro receptor potency/left shift experiments in cells stably expressing the rat's M1 receptor were performed. They revealed an inflection point value of BQCA corresponding to 306 nM, and potentiation of the agonist response up to 47-fold in presence of 10 μM of BQCA. In vivo, brain microdialysis showed a maximal brain level of 270 nM, 40 min after i.p. administration at 10 mg/kg. Based on in vitro data obtained with this dose, it can be concluded that BQCA reaches brain levels which should potentiate the agonist response about 4-fold. Behavioural data confirmed that BQCA used at 10 mg/kg attenuated scopolamine-induced memory deficit in a spontaneous alternation task. Moreover, BQCA showed no side effect at 10 mg/kg and above in spontaneous locomotion and salivation tests. The profile of BQCA observed in the present study displays a clear advantage over the M1-M3 agonist cevimeline. The present data show the therapeutic potential of the M1 receptor positive allosteric modulator BQCA for the treatment of memory deficits observed in Alzheimer's disease.