The profile of sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, in the marmoset.
1. Sabcomeline (SB-202026, 0.03 mg kg(-1), p.o.), a potent and functionally selective M1 receptor partial agonist, caused a statistically significant improvement in the performance of a visual object discrimination task by marmosets. No such improvement was seen after RS86 (0.1 mg kg(-1), p.o.). 2. Initial learning, which only required an association of object with reward and an appropriate response to be made, was not significantly affected. Reversal learning, which required both the extinction of the previously learned response and the acquisition of a new response strategy, was significantly improved after administration of sabcomeline (0.03 mg kg(-1), p.o.). 3. Sabcomeline (0.03 and 0.1 mg kg(-1), p.o.) had no significant effect on mean blood pressure measured for 2 h after administration in the conscious marmoset. 4. Sabcomeline (0.03 mg kg(-1), p.o.) caused none of the overt effects such as emesis or behaviours often seen after the administration of muscarinic agonists, e.g. face rubbing and licking. 5. This is the first study to demonstrate cognitive enhancement by a functionally selective M1 receptor partial agonist in a normal (i.e. non-cognitively impaired) non-human primate and this effect was seen at a dose which did not cause side effects. 6. Perseverative behaviour and deficient acquisition of new information are seen in patients with Alzheimer's disease (AD). Therefore the data suggest that sabcomeline might be of therapeutic benefit in the treatment of AD.
Harries
M H
MH
Neurosciences Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex.
Samson
N A
NA
Cilia
J
J
Hunter
A J
AJ
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002144:Callithrix; D005260:Female; D007097:Imines / Q000008:administration & dosage / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000008:administration & dosage / Q000494:pharmacology; D010364:Pattern Recognition, Visual / Q000187:drug effects; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013388:Succinimides / Q000008:administration & dosage / Q000494:pharmacology
D007097:Imines; D018721:Muscarinic Agonists; D010277:Parasympathomimetics; D011812:Quinuclidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013388:Succinimides; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; C109640:sabcomeline