Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer’s presenile dementia models

• Published in: Bioorganic & medicinal chemistry 2008-08, Vol.16 (15), p.7095-7101
• Main Authors: Malviya, Manish, Kumar, Y.C. Sunil, Asha, D., Chandra, J.N. Narendra Sharath, Subhash, M.N., Rangappa, K.S.
• Format: Article
• Language: English
• Subjects: Agonist; Alzheimer Disease - drug therapy; Alzheimer’s disease; Amnesia - prevention & control; Animals; Arecoline - analogs & derivatives; Arecoline - chemistry; Arecoline - pharmacology; Biological and medical sciences; Cholinergic system; Dementia; Displacement assay; Dose-Response Relationship, Drug; In vitro; In vivo; Inositol (1,4,5)-trisphosphate; Inositol 1,4,5-Trisphosphate - metabolism; Learning - drug effects; M1 receptor; Male; Medical sciences; Molecular Structure; Muscarinic Antagonists - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rat brain; Rats; Receptor, Muscarinic M1 - agonists; Scopolamine Hydrobromide - pharmacology; Structure-Activity Relationship; Synaptosomes - drug effects; Synaptosomes - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.06.053

As part of our continuing effort aimed at the development of selective, efficacious and centrally active M1 muscarinic agonists for the treatment of Alzheimer’s presenile dementia, a series of N-arylthioureas substituted 3-morpholino arecoline derivatives 9(a–j) were synthesized by using N-benzyl amino ethanol coupling with α-bromo acetyl pyridine followed by reduction and cyclization to develop a new class of M1 receptor agonists. Subsequently the synthesized compounds were subjected to in vitro radioligand M1 receptor affinity studies, IP3 formation studies and also to in vivo pharmacological evaluation of memory and learning in male Wistar rats. Derivatives with chloro ( 9f) and methoxy ( 9c) groups on the para position of the benzene ring attached to the nitrogen of thiourea showed several fold high affinity for the M1 receptor (in vitro) among all the synthesized molecules 9( a–j), and also significantly elevated IP3 levels and as well elicited beneficial effects in vivo in memory and learning models in rats (rodent memory evaluation, plus and Y maze studies).