A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H₃ receptor (H₃R) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the H₃R appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on H₃R affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the H₃R (K_i = 3.17 and 7.70 nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H₃ receptor. While its structural replacement to piperidine is also tolerated for H₃R binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the H₃R, as well as drug-like properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test results of compound 9 (structural analogue of Abbott’s A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound.

一系列具有不同调节区取代基的4-吡啶基哌嗪衍生物被证明是在纳摩尔浓度范围内有效的组胺H ₃受体（H ₃ R）配体。影响电子对H ₃ R的亲和力的最有影响的修饰是通过将吸电子部分引入远端芳香环而出现的。为了最终讨论特征性4-吡啶基哌嗪部分对H ₃ R亲和力的影响，获得了两个在基本部分上有微小修饰的环丙沙芬类似物2和3。用化合物2中的哌啶替代3中的哌嗪导致对H ₃ R（K _i分别为3.17和7.70 nM。实际上，3在该系列的所有化合物中显示出最高的拮抗特性，因此证实了我们以前的假设，即4-吡啶基哌嗪部分是与人组胺H ₃受体进行适当相互作用的关键元素。虽然其对哌啶的结构取代也可耐受H ₃ R结合，但杂芳族4-吡啶基部分似乎对适当的配体-受体相互作用至关重要。使用分子建模技术证明了负责其高亲和力的推定蛋白质-配体相互作用。此外，使用体外方法评估了选择性，在H ₃ R上的固有活性以及配体的类药物性质方法。此外，化合物9（Abbott的A-331440的结构类似物）的体内药理试验结果清楚地表明，它可能会影响所消耗的卡路里数量，因此起厌食性化合物的作用。