title: Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models.
abstract: 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 alpha-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).
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Malviya
authors.forename: Y C Sunil
authors.initials: YC
authors.lastname: Kumar
authors.forename: D
authors.initials: D
authors.lastname: Asha
authors.forename: J N Narendra Sharath
authors.initials: JN
authors.lastname: Chandra
authors.forename: M N
authors.initials: MN
authors.lastname: Subhash
authors.forename: K S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000647:Amnesia / Q000517:prevention & control; D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D012601:Scopolamine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D001115:Arecoline; D015544:Inositol 1,4,5-Trisphosphate; D012601:Scopolamine