ABSTRACT
Nine analogues of mecamylamine (2) which differ in the number and substitution pattern of methyl groups, were prepared. In four of these analogues the amine functionality is in an endo orientation. Enantiomers of 2-endo- and 2-exo-N-methylfenchylamine (25 and 26, respectively) were also prepared. The hydrochloride salts of these compounds were tested for nicotinic antagonism relative to mecamylamine in vivo and none was found to be as potent as mecamylamine, although a broad range of activity was observed. In general, methyl substituents at the C1, C2, and C7 positions of the mecamylamine structure do not appear to be significant for antagonistic activity. Methyl substituents at C3, however, appear to be very important for activity. Three sets of enantiomers of N-methylfenchylamine analogues, 28-30, possessing structural features of mecamylamine and nicotine were also prepared. These compounds were inactive as antagonists. Only a small degree of stereoselectivity was elicited in this series, less than that seen with enantiomers of nicotine. Antagonists with the exo N-methylamine functionality are slightly more active than the endo isomers. The extent to which structural modification might change lipophilicities was estimated through calculated partition coefficients; such changes alone appeared insufficient to explain differences in activities of the analogues. Lastly, a tolerance for a tertiary (dimethyl) amine functionality was demonstrated in addition to the lack of tolerance for bulkier substituents at C3 or on the nitrogen.
Subject(s)
Mecamylamine/analogs & derivatives , Nicotine/antagonists & inhibitors , Analgesia , Animals , Chemical Phenomena , Chemistry , Mecamylamine/chemical synthesis , Mecamylamine/pharmacology , Mice , Molecular Structure , Motor Activity/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Analysis of outdated clinical samples of maytansine formulated in mannitol indicated that approximately 40% of the original maytansine content had decomposed. Chromatographic examination of these samples showed the presence of one major and multiple minor decomposition products. The major decomposition product was found to be maysine, a naturally occurring maytansinoid resulting from hydrolytic elimination of the C-3 ester side chain. Four minor decomposition products were isolated with the use of HPLC. All of these decomposition products were found to possess the C-3 ester side chain. However, other structural modifications were noted, especially in the region of the C-9 carbinolamide. Two of the minor decomposition products were tentatively identified as 10-epimaytansine and 9-epimaytansine. One minor decomposition product was found to contain a hydroxyl group at the benzylic C-15 position.