Design and Synthesis of m1-Selective Muscarinic Agonists:  (R)-(−)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3‘-Methoxyphenyl)-2-propynyl)- oxime Maleate (CI-1017), a Functionally m1-Selective Muscarinic Agonist

Abstract

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

Muscarinic and nicotinic acetylcholine receptor agonists: current scenario in Alzheimer's disease therapy

“…However, they do not directly increase mAChR expression but increase the response of M4 receptors . Almost two decades ago, an experimental candidate CI‐1017 displayed improved spatial memory and exhibited dose‐limiting adverse effects only at efficacy level 100‐fold showing a possibility of improving cognition process related to cholinergic activity . The Merck candidate MK‐7622, an M1 muscarinic receptor agonist was halted prematurely at phase 2 trials with no reasons found over the literature review or the company's website .…”

“…[28] Almost two decades ago, an experimental candidate CI-1017 displayed improved spatial memory and exhibited dose-limiting adverse effects only at efficacy level 100-fold showing a possibility of improving cognition process related to cholinergic activity. [29] The Merck candidate MK-7622, an M1 muscarinic receptor agonist was halted prematurely at phase 2 trials with no reasons found over the literature review or the company's website. [30][31][32] Nicotinic receptors (nAChRs) also respond physiologically to ACh, and the a7 and a4b2 subtype expressing neurons are particularly found to be damaged in patients suffering from AD.…”

Progress in the development of β-lactams as N-Acylethanolamine Acid Amidase (NAAA) inhibitors: Synthesis and SAR study of new, potent N-O-substituted derivatives

“…The final step to achieve the N-O-substituted a-amino b-methyl b-lactam analogues started from 18 which was either submitted to a classic Mitsunobu reaction [24,25] with various alcohols to obtain the N-O-alkyl derivatives (19e29), or to a copper catalyzed coupling reaction [26] with arylboronic acids to afford the corresponding N-O-aryl b-lactams (30e39) (Scheme 2).…”

“…11.7. 4-Cyclohexylbutyl-((2S,3S)-2-methyl-1-(3-(methylsulfonyl) propoxy)-4-oxoazetidin-3-yl)carbamate(25). The reaction was carried out following the general procedure GP1 employing 18 (0.1 g, 0.33 mmol), triphenylphosphine (0.104 g, 0.40 mmol), 3-(methylsulfonyl)propan-1-ol (0.055 mL, 0.40 mmol) and DEAD (0.175 mL, 0.40 mmol).…”

The M1 Muscarinic Agonist CI-1017 Facilitates Trace Eyeblink Conditioning in Aging Rabbits and Increases the Excitability of CA1 Pyramidal Neurons

“…CI-1017 is a second generation agonist designed to selectively activate the M1 receptor while minimizing peripheral side effects (Tecle et al, 1998). It is an oxime of 1-azabicyclo[2.2.1] heptan-3-one with a 3-phenylpropargyl analog substituent, and it is identified as a relatively m1-selective partial agonist by cell metabolism, cell amplification, and second messenger assays with an overall selectivity of m1 Ն m4 Ͼm3 ϭ m5 Ͼ Ͼ m2 (Jaen et al, 1995).…”