title: M1 agonists for the treatment of Alzheimer's disease. Novel properties and clinical update.
abstract: The AF series compounds, AF102B and congeners of AF150(S), are functionally selective agonists for m1 muscarinic receptors (m1AChRs). This is shown in stable transfected CHO and PC12 cells (PC12M1) with m1m5AChRs and m1AChRs, respectively. AF102B and AF150(S) are partial agonists, but AF150, AF151, and AF151 (S) are full agonists in stimulating phosphoinositides hydrolysis or arachidonic acid release in these cells. Yet, all these compounds behave as antagonists when compared with carbachol in elevating cAMP levels. In PC12M1 cells, unlike carbachol, the AF series compounds induce only minimal to moderate neurite outgrowth. Yet, these agonists synergize strongly with NGF, which by itself mediates only a mild response. Stimulation of m1AChRs by AF102B, AF150(S) and AF151(S) in PC12M1 cells enhances secretion of beta/A4 amyloid precursor protein derivatives (APPs). The enhanced APPs secretion induced by AF102B is potentiated by NGF. AF102B also stimulates APPs secretion from rat cortical slices. Stimulation of m1AChR in PC12M1 cells with carbachol or AF102B decreases tau phosphorylation as indicated by specific tau-1 mAb and alkaline phosphatase treatment. Due to the above mentioned properties m1 agonists may be of unique value in delaying the progression of Alzheimer's disease (AD). The AF series compounds show a wide safety margin and improve memory and learning deficits in animal models for AD. There is a dearth of clinical reports on m1 agonists. These include studies on AF102B and xanomeline, another m1 selective agonist. We tested AF102B in escalating doses of 20, 40, 60 mg, tid, po, (each dose for 2 weeks) for a total of 10 weeks. This was a single-blind placebo-controlled, parallel-group study in patients with probable AD. AF102B was significantly effective at 40 and 60 mg, tid in the ADAS, ADAS-cognitive and ADAS-word recognition scales.
authors.affiliation: Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Fisher
authors.forename: E
authors.initials: E
authors.lastname: Heldman
authors.forename: D
authors.initials: D
authors.lastname: Gurwitz
authors.forename: R
authors.initials: R
authors.lastname: Haring
authors.forename: Y
authors.initials: Y
authors.lastname: Karton
authors.forename: H
authors.initials: H
authors.lastname: Meshulam
authors.forename: Z
authors.initials: Z
authors.lastname: Pittel
authors.forename: D
authors.initials: D
authors.lastname: Marciano
authors.forename: R
authors.initials: R
authors.lastname: Brandeis
authors.forename: E
authors.initials: E
authors.lastname: Sadot
authors.forename: Y
authors.initials: Y
authors.lastname: Barg
authors.forename: R
authors.initials: R
authors.lastname: Pinkas-Kramarski
authors.forename: Z
authors.initials: Z
authors.lastname: Vogel
authors.forename: I
authors.initials: I
authors.lastname: Ginzburg
authors.forename: T A
authors.initials: TA
authors.lastname: Treves
authors.forename: R
authors.initials: R
authors.lastname: Verchovsky
authors.forename: S
authors.initials: S
authors.lastname: Klimowsky
authors.forename: A D
authors.initials: AD
authors.lastname: Korczyn
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002986:Clinical Trials as Topic; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D008024:Ligands; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use; D011812:Quinuclidines / Q000627:therapeutic use; D051381:Rats; D011950:Receptors, Cholinergic / Q000502:physiology; D015398:Signal Transduction; D013830:Thiadiazoles / Q000737:chemistry / Q000627:therapeutic use; D013876:Thiophenes; D016875:tau Proteins / Q000378:metabolism
chemical_list: D008024:Ligands; D018721:Muscarinic Agonists; D009414:Nerve Growth Factors; D011725:Pyridines; D011812:Quinuclidines; D011950:Receptors, Cholinergic; D013830:Thiadiazoles; D013876:Thiophenes; D016875:tau Proteins; C075257:xanomeline; D019204:GTP-Binding Proteins; C059240:cevimeline