Structural manipulation of polycyclic piperazinyl imide serotonergic agents led to the synthesis of compound 8, 2-[4-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-4, 4a,5,5a,6,6a-hexahydro-4,6-ethenocycloprop[f]isoindole-1,3(2H,3 aH)-dione, which demonstrated good H1-antagonist activity. Substitution of a xanthinyl moiety for the polycyclic imide group led to the identification of novel xanthinyl-substituted piperazinyl and piperidinyl derivatives with potent antihistamine H1-activity without the undesirable antidopaminergic activity of 8. One compound, 24, 7-[3-[4-(diphenylmethoxy)-1-piperidinyl]propyl]- 3,7-dihydro-1,3-dimethyl-1H-pyrine-2,6-dione (WY-49051), is a potent, orally active H1-antagonist with a long duration of action and a favorable central nervous system profile.