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 (C₂₉H₄₂O₄N)⁺Cl⁻] was determined. The molecule forms colourless tetragonal crystals; the space group is P4₁2₁2₁ with eight molecules per unit cell of dimensions a = 11.507(2) Å and c = 41.952(9) Å. 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.