Yates S L, Tedford C E, Gregory R, Pawlowski G P, Handley M K, Boyd D L, Hough L B
Gliatech Inc., Cleveland, OH 44122, USA.
Biochem Pharmacol. 1999 May 1;57(9):1059-66. doi: 10.1016/s0006-2952(98)00378-5.
The H3 antagonist thioperamide is thought to act on brain H3 autoreceptors to increase both the release and metabolism of neuronal histamine (HA). Our studies investigated the effects of several new brain-penetrating H3 antagonists on rat cerebral cortical levels of the HA metabolite tele-methylhistamine (t-MH). Animals were pretreated with H3 antagonists (0.3 to 30 mg/kg; 1-4 hr; i.p.) in the presence or absence of the monoamine oxidase inhibitor pargyline to prevent metabolism of t-MH. Cortical t-MH levels were measured by both radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS). Pargyline (60 mg/kg; 1 hr; i.p.) produced an approximately 2-fold increase in t-MH levels as measured by either GC-MS or RIA. Thioperamide (+/- pargyline) increased t-MH levels as measured by both GC-MS and RIA. In contrast, neither 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT-2016) (+/- pargyline), 4-(6-cyclohexylhex-cis-3-enyl)imidazole (GT-2227) (+/- pargyline), nor clobenpropit (minus pargyline) increased t-MH levels as measured by GC-MS. A good agreement was found between t-MH levels as determined by either RIA or GC-MS except after treatment with GT-2016, which increased apparent t-MH brain levels according to the former but not the latter method. Subsequent studies suggest the in vivo formation of a GT-2016 metabolite, which can cross-react in the t-MH RIA. Although all H3 receptor antagonists studied to date seem capable of enhancing brain HA release, only thioperamide presently was found to enhance cortical t-MH levels. Thus, H3 receptor antagonists may differentially affect HA release and turnover, and brain t-MH levels may not be reliable predictors of H3 agonist, partial agonist, or antagonist in vivo activity.
H3拮抗剂硫代哌酰胺被认为作用于脑内H3自身受体，以增加神经元组胺（HA）的释放和代谢。我们的研究调查了几种新型脑渗透性H3拮抗剂对大鼠大脑皮层中HA代谢产物3-甲基组胺（t-MH）水平的影响。在存在或不存在单胺氧化酶抑制剂帕吉林的情况下，给动物预先注射H3拮抗剂（0.3至30 mg/kg；1 - 4小时；腹腔注射），以防止t-MH的代谢。通过放射免疫分析（RIA）和气相色谱-质谱联用（GC-MS）测量皮层t-MH水平。帕吉林（60 mg/kg；1小时；腹腔注射）使通过GC-MS或RIA测量的t-MH水平增加约2倍。硫代哌酰胺（±帕吉林）通过GC-MS和RIA测量均增加了t-MH水平。相比之下，5-环己基-1-（4-咪唑-4-基哌啶基）戊-1-酮（GT-2016）（±帕吉林）、4-（6-环己基己-顺-3-烯基）咪唑（GT-2227）（±帕吉林）以及氯苯丙哌嗪（-帕吉林）通过GC-MS测量均未增加t-MH水平。除了用GT-2016处理后，通过RIA和GC-MS测定的t-MH水平之间发现有良好的一致性，根据前者方法，GT-2016增加了t-MH在脑中的表观水平，但后者方法未显示增加。后续研究表明在体内形成了一种GT-2016代谢产物，它能在t-MH RIA中发生交叉反应。尽管迄今为止研究的所有H3受体拮抗剂似乎都能够增强脑内HA释放，但目前仅发现硫代哌酰胺能提高皮层t-MH水平。因此，H3受体拮抗剂可能对HA释放和周转有不同影响，并且脑内t-MH水平可能不是体内H3激动剂、部分激动剂或拮抗剂活性的可靠预测指标。
