Dahl S G, Hough E, Hals P A
Biochem Pharmacol. 1986 Apr 15;35(8):1263-9. doi: 10.1016/0006-2952(86)90269-8.
The solid state molecular structures of methoxypromazine and N-monodesmethyl chlorpromazine sulphoxide were determined by X-ray crystallography, as an extension of previous studies on the molecular structures of chlorpromazine sulphoxide and methotrimeprazine sulphoxide. The binding affinities of phenothiazine drugs and metabolites with known crystal structures to dopaminergic, alpha adrenergic and muscarinic cholinergic receptors in rat brain were examined using radio-ligand binding techniques. Comparison of their solid state molecular structures and potencies in neurotransmitter receptor binding reveals that these compounds exist in two different conformations: One, associated with low biological activity, has an angle between the planes of the two aryl rings in the range of 155-160 degrees, and a torsion angle of -80 to -84 degrees around the N(10)-C bond of the side-chain, calculated from the substituted benzene ring. In the other conformation, which is found in the biologically active derivatives, the angle between the planes of the two aryl rings is in the range of 134-145 degrees, and the torsion angle around the N(10)-C bond of the side-chain is in the range of 64-69 degrees or 129-144 degrees. The "active" and "inactive" conformations thus have the side-chain on opposite sides of the ring system.
作为对先前关于氯丙嗪亚砜和甲硫哒嗪亚砜分子结构研究的扩展，通过X射线晶体学确定了甲氧丙嗪和N-单去甲基氯丙嗪亚砜的固态分子结构。使用放射性配体结合技术研究了具有已知晶体结构的吩噻嗪类药物及其代谢物与大鼠脑中多巴胺能、α肾上腺素能和毒蕈碱胆碱能受体的结合亲和力。比较它们的固态分子结构和在神经递质受体结合中的效力发现，这些化合物存在两种不同的构象：一种与低生物活性相关，两个芳环平面之间的夹角在155-160度范围内，从取代苯环计算，侧链N(10)-C键周围的扭转角为-80至-84度。在生物活性衍生物中发现的另一种构象中，两个芳环平面之间的夹角在134-145度范围内，侧链N(10)-C键周围的扭转角在64-69度或129-144度范围内。因此，“活性”和“非活性”构象的侧链位于环系统的相对两侧。
