Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition.
Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and in vivo inhibition of cholinesterase. Compound 4a was also effective in alleviating scopolamine induced amnesia in a rat passive avoidance model.
Verheijen
Jeroen C
JC
Sention Inc., 1 Richmond Square, Providence, RI 02906, USA. verheij@wyeth.com
Wiig
Kjesten A
KA
Du
Shoucheng
S
Connors
Stacie L
SL
Martin
Ashley N
AN
Ferreira
Jennifer P
JP
Slepnev
Vladimir I
VI
Kochendörfer
Ulrike
U
D000284:Administration, Oral; D000647:Amnesia / Q000188:drug therapy; D000662:Amphetamines / Q000737:chemistry; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D048448:Phenylcarbamates / Q000737:chemistry; D051381:Rats; D000068836:Rivastigmine
D000662:Amphetamines; D001679:Biogenic Amines; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000068836:Rivastigmine