Column chromatography of easy available (f)-physovenine (2) on cellulose triacetate afforded (-)-and (+)-physovenine (2a and 2b, resp.). Alkaloids 2a, h required for pharmacological testing were prepared from eserolines (3a, b) by an improved procedure. Natural (-)-physovenine (2a) was equally potent in inhibiting AChE and RChE in uitro as natural physostigmine (la), and twice as potent as the unnatural antipode 2b against AChE and 14 times as potent against BChE. Several carbarnate analogs of 2a were at least as potent as the former compound in these assays. None of the compounds tested did bind to different opiate receptor or serotonine receptor preparations. Most of the compounds tested had considerable analgesic activity in the Writhing test.In search of centrally acting agents potentially useful for treating cholinergic disorders, particularly those manifested by Alzheimer's disease, we have embarked on a re-evaluation of the alkaloids from the seeds of Physostigma venenosum [la-]. Two of the alkaloids, (-)-physostigmine (la; see Scheme) and (-)-physovenine (2a), were reported to have potent anti-acetylcholinesterase (AChE) activity when assayed in vitro, measuring inhibition of AChE obtained from human erythrocytes [2], and l a is medically used to reduce intraocular tension in glaucoma, in the treatment of intestinal atony, and in the treatment of urinary retention [3]. Modification of the carbarnate group and of the Me-N(l) group in l a has afforded several potent analogs [4] [5]. We now have extended this research to another study of the lesser known (-)-physovenine (2a) and some of its carbarnate-ester analogs and of the unnatural enantiomer (+)-physovenine (2b). Natural 2a was isolated from the basic extracts of Physostigma venenosum in 1911 [6] and its structure proposed on the basis of spectral data [7] and proven to be correct by a total synthesis of racemate 2 [8]. The (3aS)-configuration of 2a and the (3aR)-configuration of antipode 2b was elaborated by their enantiospecific synthesis from (-)-physiostigmine (la) [9] and (+)-physiostigmine (la), respectively [2].
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