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A novel series of potent 5-HT(7) receptor antagonists was identified using an automated virtual screen. Structure-activity studies resulted in analogues 4 and 5, which were evaluated for binding, functional response, and in vitro and in vivo 5-HT(7) affinity. 5 showed good potency in the guinea pig ileum assay (inhibition of the contractile response to 5-HT) and the quail brainstem assay (blockade of the response to 5-HT). In the guinea pig pre- and post-synaptic binding assay, compound 5 displayed excellent affinity for the 5-HT(7) receptor. Functional activity in terms of antagonism of light-induced retinal degeneration in the rhodopsin kinase (pLID.T7) transgenic mouse model was tested and found to be strongly correlated with 5-HT(7) receptor binding. In vivo efficacy was tested in two screening models. The 5-HT(7) agonist mCPP led to hypolocomotion of mice following i.p. administration. Compound 5 significantly reversed mCPP-induced hypolocomotion. In addition, compound 5 was evaluated for its ability to improve performance in the rotarod test in a mouse model of Huntington’s disease (HD). This latter model has been validated as a model for selective cognitive impairment in HD. 5 showed good efficacy in this test, supporting the 5-HT(7) receptor hypothesis of HD-induced memory impairment.package jsonschema

import (
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