New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids.
During this study, one new coumarin; 7-O-beta-D-glucopyranoside-2H-1-benzopyran-2-one (1) and three quinoline alkaloids; 3-hydroxy, 2, 2, 6-trimethyl-3, 4, 5, 6-tetrahydro-2H-pyrano[3,2-c] quinoline 5-one (2), ribalinine (3) and methyl isoplatydesmine (4) were isolated from the aerial parts of Skimmia laureola and their structures established by spectroscopic studies. Compounds 2-4 were found to be linear mixed type inhibitors of acetylcholinesterase (K(i) = 110.0, 30.0 and 30.0 microM, respectively). Compounds 2 and 3 were also found to be linear mixed type inhibitors of butyrylcholinesterase, while compound 4 was a noncompetitive inhibitor of the enzyme (K(i) = 90.0, 70.0 and 19.0 microM, respectively). The inhibition of acetyl- and butyryl-cholinesterase enzymes persists as the most promising therapeutic strategy for activating the impaired cholinergic functions in Alzheimer's disease and related dementias. Compound 4 also showed dose-dependent spasmolytic activity in the isolated rabbit jejunum intestinal preparation by relaxing the spontaneous (EC50 = 0.1 mg/mL) and K(+)-induced contractions (EC50 = 0.4 mg/mL), suggesting that the spasmolytic effect of compound 4 is mediated through the blockade of voltage-dependent Ca2+ channels.
Atta-ur-Rahman
Dr. Panjwani Center for Molecular Medicine and Drug Research, University of Karachi, Karachi 75270, Pakistan. chairman@hec.gov.pk
Khalid
Asaad
A
Sultana
Nighat
N
Ghayur
M Nabeel
MN
Mesaik
M Ahmed
MA
Khan
M Riaz
MR
Gilani
Anwar H
AH
Choudhary
M Iqbal
MI
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007583:Jejunum / Q000187:drug effects; D007700:Kinetics; D011804:Quinolines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011817:Rabbits
D000470:Alkaloids; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002800:Cholinesterase Inhibitors; D011804:Quinolines; D002802:Cholinesterases