Antihistaminic and other pharmacological actions both in vitro and in vivo were evaluated on 18 compounds involving octahydro-2H-pyrido[1, 2-a]pyrazine (I), decahydropyrido[1, 2-d][1, 4]diazepine (II), and decahydropyrido[1, 2-a][1, 4]diazepine (III) derivatives, and correlation between chemical structure and antihistaminic activity was investigated. Since it was found that the most effective gross structure and substituent was I and a benzhydryl grouping, respectively, 2-benzhydryloctahydro-2H-pyrido[1, 2-a]pyrazine (I-2) was established as the most powerful agent among these compounds. This was demonstrated by the fact that I-2 exhibited a high antihistaminic potency both in vitro and in vivo, as well as a strong adsorbability to guinea pig ileum which was estimated to be equivalent to diphenhydramine (IV). Furthermore, I-2 gave a lower acute toxicity than IV or homochlorcyclizine and was more effective than IV not only in antiserotoninic and anticholinergic activities but also in anti-barium activity. A weak surface anesthetic effect of I-2 was also observed on the cornea of a guinea pig.
