NEW 5-HT3 (SEROTONIN-3) RECEPTOR ANTAGONISTS .2. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PYRIMIDO[1,6-ALPHA]INDOLES

A series of pyrimido[1,6-alpha]indol-1(2H)-ones was prepared and evalu ated for 5-HT3 receptor antagonist activity. The compounds in this ser ies were regarded as bioisosters of the pyrido[1,2-alpha]indol-6(7H)-o nes previously reported. High potency was found for compounds having 5 -methyl substituents on both the pyrimido[1,6-alpha]indole ring and th e imidazole ring. Optimized members of this series, 8b and (+)-26a, we re potent 5-HT3 receptor antagonists as determined by measuring inhibi tion of the Bezold-Jarisch reflex in anesthetized rats (ED(50) 0.6 and 0.8 mu g/kg i.v., respectively), being equipotent to or more potent t han FK 1052 (1) in the previous paper and 20- to 30-fold more potent t han ondansetron (2).