MEDICINAL CHEMISTRY OF MUSCARINIC AGONISTS FOR THE TREATMENT OF DEMENTIA DISORDERS

Alzheimer disease (AD) is a neurodegenerative disorder lacking an effe ctive therapy. The etiology is controversial and among different drug strategies, the cholinergic approach has gained great interest owing t o biochemical and pharmacological evidence of the crucial role of acet ycholine in cognitive functions. Several attempts exploiting the boost ing of the cholinergic system are currently under way. Inhibitors of t he acetylcholinesterase enzyme sustain the availability of the natural transmitter by limiting its removal from the synapse. In a different approach, exogenous agonists may substitute acetylcholine itself. In t his way the issue of the extensive cholinergic cell loss occurring in AD and leading to a reduction of cholinergic functions, could be advan tageously bypassed. Moreover the discovery of different muscarinic rec eptor subtypes, most notably the M1 subtype as that involved in the po stsynaptic transmission, has offered new opportunities to face the pro blem in a very specific way. In this line of research, we have now ide ntified BIMC 182 as a new functionally selective M1 agonist. Whereas i ts affinity for the different receptor subtypes is almost similar (rad ioreceptor binding), its functional selectivity is pointed out by spec ific ''in vitro'' models. BIMC 182 behaves as a full agonist at M1 (ra t superior cervical ganglion, pD2 4.8) and as a partial agonist at M2 and M3 sites (g.p. heart pD(2) = 5.4 and g.p. ileum pD(2) = 4.5). The agonist profile is further confirmed in hm1 transfected CHO cells wher e the compound stimulates PI turnover. BIMC 182 penetrates well the br ain as shown by the increase in the energy of the low frequency band ( theta waves) in the cortical EEG of rabbits (3 mg/kg i.v.). In the sam e range of doses the compound antagonises the scopolamine induced amne sia in rats (passive avoidance and Morris water maze tests).