Histamine is a transmitter that activates the four receptors H₁R to H₄R. The H₃R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1‐(2,3‐dihydro‐1‐benzofuran‐2‐yl)methylpiperazines (LINS01 compounds) have the selectivity for the H₃R over the H₄R. Here, we describe their pharmacological properties at the human H₁R and H₂R in parallel with the H₃R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H₃R‐induced histamine responses, but no inhibition of H₂R‐induced responses was seen. Three compounds were weakly able to inhibit H₁R‐induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N‐methyl group improves H₃R affinity while the N‐phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.

中文翻译：

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LINS01化合物在人组胺H1，H2和H3受体上的药理和SAR分析

组胺是激活的四种受体h的发射机₁ R键ħ ₄ R.为H ₃中的R神经系统作为自身受体和heteroreceptor，和控制神经递质的释放被发现，使之成为神经精神病症的潜在药物靶。我们先前已报道了1-（2,3-二氢-1-苯并呋喃-2-基）methylpiperazines（LINS01化合物）具有对H的选择性₃ R经由为H ₄ R.在这里，我们描述了其药理学性质，在人类H ₁ R和H ₂ R与H ₃平行R，因此可通过报告基因分析全面分析作为组胺受体配体的这些化合物。九种LINS01化合物中有八种抑制H ₃ R诱导的组胺反应，但没有抑制H ₂ R诱导的反应。三种化合物几乎不能抑制H ₁ R诱导的反应。在任何受体上均未观察到对任何化合物的激动剂反应。SAR分析表明，N-甲基可改善H ₃ R亲和力，而N-苯基则有害。甲氧基衍生物LINS01009具有最高的亲和力。