Analgesic activity of the epimeric tropane analogs of meperidine. Physical and pharmacological study

Abstract

Condensation of cis-N-benzyl-2,5-bis(chloromethyl)pyrrolidine (6) and phenylacetonitrile afforded a mixture of epimers 7 and 8. Compound 8 was readily converted to the meperidine analog 1 prepared earlier by Bell and Archer. Compound 7 was converted to a new tropane analog of meperidine, compound 3. The ED50 of 1 and 3 in the D'Amour-Smith "tail flick" test for narcotic type analgesia, which differs by a factor of only 3 or 4 potency, supports the accumulated data that suggest that the analgesic activity of the meperidine type is not very sensitive to the conformation of the phenyl group in 4-phenylpiperidines. A proton and 13C magnetic resonance spectral comparison of 1 and 3, as well as a reevaluation of the conformational requirements of 17-19, leads to the conclusion that the differences in conformation of 1,3,17, and 18 are due to the varying degrees of flattening of piperidine ring. The 1H NMR and 13C NMR data are not consistent with the boat conformation suggested earlier for compound 17.

3-Aminotropane-3-carboxylic acids. Preparation and properties

“…Similar differences have been found in the hydrolysis and esterification of 3a-and 3 P-tropane carboxynitriles (21). Furthermore the resistance to hydrolysis of 4-isopropyl-and 4-tert-butyl-1-amino-1-carboxynitrile hydrochlorides (a-and P-isomers) has been used as a clue to determine the configuration of the corresponding amino acids (22).…”

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 1. Glycolates

“…8 In the specific case of the amino alcohol esters, the importance of amino alcohol stereochemistry is shown by the fact that (-)-3-quinuclidinyl benzilate9 is 20 times more potent than the (+) isomer and that esters of 3atropanol (such as atropine) are more potent than their 3/3-epimers.10,11 Similar stereochemical effects have been observed in our laboratories with other tropane alkaloids. [12][13][14] The importance of the glycolic acid stereochemistry is illustrated by the fact that the 2-dimethylaminoethyl ester of (R)-H-cyclohexylphenylglycolic acid is 100 times more potent than the ester of the (S)-(+)-acid15 and similar significant differences have been reported for other esters of these acids. 16,17 The specific glycolic acids used by us were selected primarily because earlier workers had observed anticholinergic activity in esters of these acids with other amino alcohols.…”

Conformational re-analysis of (+)-meptazinol: an opioid with mixed analgesic pharmacophores

“…The two different conformers of (+)-meptazinol (Conformer-I and -II) were obtained by molecular dynamics from NOESY and TOCSY spectra. Several conformationally constrained aromatic substituted piperidines [6][7][8][9][10][11] were sketched in SYBYL according to the reported preferred con-formers with all basic nitrogen atoms protonated. The initial structures were firstly minimized by Tripos force field with Gasteiger-Huckel charges, followed by random searches to ensure their stable conformations by default settings.…”