Loza M I, Sanz F, Cadavid M I, Honrubia M, Orallo F, Fontenla J A, Calleja J M, Dot T, Manaut F, Cid M M
Department of Farmacologiá, Universidad de Santiago, Santiago de Compostela, Spain.
J Pharm Sci. 1993 Nov;82(11):1090-3. doi: 10.1002/jps.2600821105.
A series of cyproheptadine related compounds was synthesized and tested pharmacologically. In comparison with cyproheptadine, these compounds do not have a central ring and some contain groups other than N-methyl. Synthesis was carried out with low-valent titanium to generate the exocyclic double bond. The serotoninergic activity of the compounds was determined by standard determination of pA2 (-log of the motor concentration of antagonist required to maintain a constant response when concentration of agonist is doubled) for the inhibition of serotonin-induced contractions in rat stomach fundus. Two of the nitrogen-containing compounds were active, but their activities were lower than that of cyproheptadine. Structure-activity relationships were studied by Mulliken net charges, molecular electrostatic potentials, and conformational analysis; activities are better correlated with electrostatic potentials than with net charges. The decrease in potency of the open cyproheptadine analogues may be due to "dilution" of the active conformer as the result of their conformational flexibility.
合成了一系列与赛庚啶相关的化合物，并进行了药理测试。与赛庚啶相比，这些化合物没有中心环，有些还含有除N - 甲基以外的基团。用低价钛进行合成以生成环外双键。通过标准测定pA2（当激动剂浓度加倍时维持恒定反应所需拮抗剂的运动浓度的负对数）来确定化合物对大鼠胃底血清素诱导收缩的抑制作用，从而测定化合物的血清素能活性。两种含氮化合物具有活性，但其活性低于赛庚啶。通过穆利肯净电荷、分子静电势和构象分析研究了构效关系；活性与静电势的相关性比与净电荷的相关性更好。开放型赛庚啶类似物效力的降低可能是由于其构象灵活性导致活性构象体的“稀释”。
