Molecular Determinants for Drug-Receptor Interactions. Part 14. X-Ray Molecular Structure and Theoretical Conformational (MNDO, MM2) Studies of the Narcotic Dualist Buprenorphine Hydrochloride

The X-ray molecular structure of buprenorphine hydrochloride [(C29H4244N)+Cl-] was determined. The molecule forms colourless tetragonal crystals; the space group is P4(1)2(1)2(1) with eight molecules per unit cell of dimensions a = 11.507 (2) angstrom and c = 41.952 (9) angstrom. The structure was determined by direct methods and refined by the full-matrix least-squares procedure to R = 0.056 for 2251 observed reflections. The protonated buprenorphine (BPNH+) in the solid state adopts the T-shape form typical of benzomorphan compounds; the substituent group at the N atom is in the equatorial configuration and the cyclopropylmethyl side-chain is almost perpendicular to the piperidine ring. Theoretical studies of the conformations and the rotational energetics of BPNH+ were performed using both the semiquantitative MNDO and the force field (MM2) methods. The latter method predicted four low energy conformations about the N-C(21) and C(21)-C(22) bonds. Two of these were more significantly populated (59% and 30%). They may easily interconvert through only a single torsional process. The less-populated (30%) conformation was consistent with that adopted in the solid state. The MNDO method predicted different low energy conformations of the N-cyclopropylmethyl moiety. Neither method reproduced the favoured torsional angles adopted by the structurally analogous naltrexone molecule which has the opposite pharmacological profile.