Progress in medicinal chemistry of novel selective muscarinic agonists.
Rigid analogs of acetylcholine (ACh) were designed for selective actions at muscarinic receptor subtypes. AF102B, AF125, AF150 and AF151 are such rigid analogs of ACh. Whilst AF125 is an M2 > M1 agonist, AF102B, AF150 and AF151 are centrally active M1 agonists. AF102B has a unique agonistic profile showing, inter alia, only part of the M1 electrophysiology of ACh and unusual binding parameters to mAChRs. AF150 and AF151 are more efficacious agonists than AF102B for M1 AChRs in rat cortex and in CHO cells stably transfected with the m1 AChR subtype. In various animal models for Alzheimer's disease (AD) all three agonists (AF102B, AF150 and AF151), and in particular AF102B, exhibited positive effects on mnemonic processes and a wide safety margin. Such agonists, and especially AF102B, can be considered as a rational treatment strategy in AD. Here we review some current features of these compounds, which may be relevant to a rational treatment strategy in AD. Comparison is made, whenever possible, with some new and old muscarinic agonists.
Israel Institute for Biological Research, Ness-Ziona.
A
A
Fisher
Y
Y
Karton
E
E
Heldman
D
D
Gurwitz
R
R
Haring
H
H
Meshulam
R
R
Brandeis
Z
Z
Pittel
Y
Y
Segall
D
D
Marciano
D000109:Acetylcholine / Q000031:analogs & derivatives; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002626:Chemistry, Pharmaceutical; D006801:Humans; D010277:Parasympathomimetics / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013876:Thiophenes
D010277:Parasympathomimetics; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D013876:Thiophenes; C059240:cevimeline; D000109:Acetylcholine