Back to Search
Start Over
M1 agonists for the treatment of Alzheimer's disease. Novel properties and clinical update.
- Source :
-
Annals of the New York Academy of Sciences [Ann N Y Acad Sci] 1996 Jan 17; Vol. 777, pp. 189-96. - Publication Year :
- 1996
-
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.
- Subjects :
- Animals
Clinical Trials as Topic
GTP-Binding Proteins physiology
Humans
Ligands
Muscarinic Agonists chemistry
Muscarinic Agonists pharmacology
Nerve Growth Factors pharmacology
PC12 Cells drug effects
PC12 Cells metabolism
Phosphorylation
Pyridines chemistry
Pyridines therapeutic use
Quinuclidines therapeutic use
Rats
Receptors, Cholinergic physiology
Signal Transduction
Thiadiazoles chemistry
Thiadiazoles therapeutic use
tau Proteins metabolism
Alzheimer Disease drug therapy
Muscarinic Agonists therapeutic use
Thiophenes
Subjects
Details
- Language :
- English
- ISSN :
- 0077-8923
- Volume :
- 777
- Database :
- MEDLINE
- Journal :
- Annals of the New York Academy of Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 8624083
- Full Text :
- https://doi.org/10.1111/j.1749-6632.1996.tb34418.x