Crystal-Structure of Naltrexone Hydrochloride: Implications for Location of the Nicotinic Receptor Noncompetitive Inhibitor Binding Site

Abstract

The opiate receptor antagonist naltrexone is also a non-competitive blocker of the nicotinic acetylcholine receptor ion channel complex. This blockade is usually thought to be due to physical occlusion of the channel pore. However, the most recent structural data for the nicotinic receptor show that the pore is generally 20-25 A in diameter, with a much narrower section in the plane of the membrane which is presumed to be the gating region. We have completed a single-crystal X-ray structure determination of naltrexone hydrochloride, (C₂₀H₂₄NO₄)⁺Cl^-.4H₂O, at room temperature. Crystals are orthorhombic, P2₁2₁2₁, a 18.099(5), b 15.926(6), c 7.768(11) A, Z 4; the structure was refined to a residual of 0.056 for 1988 'observed' reflections. The maximal dimension of this molecule (c. 11 - 6 A) suggests that physical occlusion of the channel pore can only occur if binding is directly in the gating region.