Oxotremorine analogs

All members of a series of oxotremorine analog (184a-e), in which the pyrrolidone ring iscontracted to a j3-lactam moiety (217), demonstrated uniformly weak cholinergic effects. 

The stereoisomers of some oxotremorine analogs containing two chiral centers and acting as oxotremorine antagonists show in vivo (tremorolytic activity) stereoselectivity ratios as high as 1 to 200. ... 

Oxotremorine has a pATa of 7.91 and it is mostly protonated at physiological pH (7.4). The activity of this prototype is believed to be associated with the protonated form. Most oxotremorine analogs do not differ significantly from oxotremorine in their basicity and are also protonated at pH 7.4. Thus, the differences in activity between the analogs of oxotremorine cannot be ascribed to this property. In terms of lipophilicity it seems that secondary and tertiary analogs of oxotremorine are not very different and are... 

Concomitant ring opening of lactone 275 and esterification of the resulting a-hydroxy acid with trimethylsilyl iodide in ethanol produces iodoester 296. Subsequent treatment with propargylamine affords pyrrolidinone 297 in 45% overall yield from ( S)-malic acid. The product is used as an intermediate for the preparation of hydroxyl-containing oxotremorine analogs potentially useful for the treatment of senile dementia [40]. 

Other cholinergic agonists have no therapeutic use. Muscarine (4.3) is an alkaloid of the mushroom Anumita muscaria muscarone (4.9) is its semisynthetic analog. Pilocarpine (2.2) is found in the leaves of a shrub and can be used to increase salivation or sweating. Arecoline (4.10) is also an alkaloid, and occurs in the betel nut that is used as a mild euphoriant in India and Southeast Asia. Finally, oxotremorine (4.11) is a synthetic experimental agent that produces tremors and is helpful in the study of antiparkinsonian drugs. 

Table 2.3 Muscarinic Activities of Oxotremorine Congeners and Analogs Containing Trimethylammonium or Pyrrolidine Groups...

In a series of oxotremorine and oxotremo-rine-M (196) analogs (197,198), all compounds studied (tertiary and quaternary amines) demonstrated analgesic effects in neurogenic and inflammatory pain models (233). It was concluded that these compounds were acting as muscarinic analgesics. The antinociceptive effects were blocked by atropine but not by naloxone or mecamylamine. Members of the series varied as to classic muscarinic agonist effects (e.g., salivation). 

Tertiary 2-, 3-, and 4-haloalkylamine analog of oxotremorine were investigated in mice as prodrugs of muscarinic agonists (237) (Ta-... 

FIGURE 16.25 Oxotremorine yields ring-opened and ring-extended analogs. ... 

Nordstrom and coworkers showed that the analog of oxotremorine, A-methyl-A-(l-methyl-4-pyrrolidono-2-butynyl) acetamide, acts as a postsynaptic agonist in various muscarinic test models. However, this analog is also an antagonist of presynaptic muscarinic receptors. Such diversity in receptor action may contribute to the differences in overall activity of analogs in this series. 

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