Abstract
We report the synthesis of new compounds 4-35 based on structural modifications of different moieties of previously described lead UCM-2550. The new nonpiperazine derivatives, representing second-generation agonists, were assessed for binding affinity, selectivity, and functional activity at the 5-HT(1A) receptor (5-HT(1A)R). Computational β(2)-based homology models of the ligand-receptor complexes were used to explain the observed structure-affinity relationships. Selected candidates were also evaluated for their potential in vitro and in vivo neuroprotective properties. Interestingly, compound 26 (2-{6-[(3,4-dihydro-2H-chromen-2-ylmethyl)amino]hexyl}tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione) has been characterized as a high-affinity and potent 5-HT(1A)R agonist (K(i) = 5.9 nM, EC(50) = 21.8 nM) and exhibits neuroprotective effect in neurotoxicity assays in primary cell cultures from rat hippocampus and in the MCAO model of focal cerebral ischemia in rats.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Benzopyrans / chemical synthesis*
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Benzopyrans / chemistry
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Benzopyrans / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Death
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Cells, Cultured
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Cerebral Infarction / drug therapy
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Cerebral Infarction / pathology
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Hippocampus / cytology
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Ischemic Attack, Transient / drug therapy*
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Ischemic Attack, Transient / pathology
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Models, Molecular
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Molecular Sequence Data
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Neurons / cytology
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Neurons / drug effects
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Radioligand Assay
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Rats
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Receptor, Serotonin, 5-HT1A / metabolism*
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Serotonin 5-HT1 Receptor Agonists / chemical synthesis*
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Serotonin 5-HT1 Receptor Agonists / chemistry
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Serotonin 5-HT1 Receptor Agonists / pharmacology
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Structure-Activity Relationship
Substances
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2-(6-((3,4-dihydro-2H-chromen-2-ylmethyl)amino)hexyl)tetrahydro-1H-pyrrolo(1,2-c)imidazole-1,3(2H)-dione
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Benzopyrans
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Bridged Bicyclo Compounds, Heterocyclic
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Neuroprotective Agents
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Serotonin 5-HT1 Receptor Agonists
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Receptor, Serotonin, 5-HT1A