X-ray molecular structures and theoretical conformational studies of narcotic analgesics alpha-(-)-N-cis-3-chloroallyl-normetazocine, ethylketazocine, and ketazocine.
The X-ray molecular structures of the narcotic analgesics alpha-(-)-2-cis-3-chlorallyl-2'-hydroxy-5,9-dimethyl-6,7-benzomorp han (1) and alpha-(+-)-2-cyclopropylmethyl-2'-hydroxy-5-ethyl-9-methyl-8-oxo-6,7- benzomorphan (ethylketazocine, 2) were determined. The structures and conformations in the crystal were compared and discussed with respect to that of alpha-(+-)-2-cyclopropylmethyl-2'-hydroxy-5,9-dimethyl-8- oxo-6,7-benzomorfan (ketazocine, 3) and those of 15 analogous compounds of the 2'-hydroxy-6,7-benzomorphan series whose structures were previously determined by X-ray analysis. Molecular modeling routines for 1, 2, and 3 produced configurations (N-equatorial) and conformations (distorted chair) of the piperidine ring that were in agreement with those found in the solids. Theoretical studies of the conformations and the rotational energetics of 1, 2, and 3 as cationic species were performed by both the force field (MM2) and the semiquantitative (AM1) methods. The latter method predicted three low energy conformations about N--C(12) and C(12)--C(13) bonds, one of these being more significantly populated (60-68%). The AM1 results were not reproduced by the MM2 method, which predicted four low energy conformations. An interesting common feature of 1, 2, and 3 that was noted with both methods was the restricted interconversion route from the conformational state to another through rotations about the C(12)--C(13) bond. The conformational results were discussed in terms of a working hypothesis for regulation of relative mu and kappa analgesic activities of benzomorphans.
Bandoli
G
G
Dipartimento di Scienze Chimiche, Facoltà di Farmacia, Università di Cantania, Italy.
Grassi
A
A
Pappalardo
G C
GC
D000701:Analgesics, Opioid / Q000737:chemistry*; D001575:Benzomorphans / Q000737:chemistry*; D003461:Crystallography; D016314:Ethylketocyclazocine / Q000031:analogs & derivatives* / Q000737:chemistry*; D008968:Molecular Conformation; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D001575:Benzomorphans; C083265:3-chlorallyl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan; D016314:Ethylketocyclazocine; C012395:ketazocine