Abstract
We report the synthesis of a new set of compounds of general structure I (1-20) with structural modifications in the pharmacophoric elements of the previously reported lead UCM-5600. The new derivatives have been evaluated for binding affinity at 5-HT(7) and 5-HT(1A) receptors. The influence of the different structural features in terms of 5-HT(7)/5-HT(1A) receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and beta(2)-based 3-D models of these receptors. Compound 18 (HYD(1) = 1,3-dihydro-2H-indol-2-one; spacer = -(CH(2))(4)-; HYD(2) + HYD(3) = 3,4-dihydroisoquinolin-2(1H)-yl) exhibits high 5-HT(7)R affinity (K(i) = 7 nM) and selectivity over the 5-HT(1A)R (31-fold), and has been characterized as a partial agonist of the human 5-HT(7)R.
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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Cell Line
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Cricetinae
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Cricetulus
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Drug Partial Agonism
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Ligands
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Models, Molecular
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Molecular Sequence Data
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Radioligand Assay
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Receptor, Serotonin, 5-HT1A / metabolism*
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Receptors, Serotonin / metabolism*
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Serotonin 5-HT1 Receptor Agonists
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Serotonin 5-HT1 Receptor Antagonists
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology
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Serotonin Receptor Agonists / chemical synthesis*
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Serotonin Receptor Agonists / chemistry
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Serotonin Receptor Agonists / pharmacology
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Structure-Activity Relationship
Substances
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1-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-1,3-dihydro-2H-indol-2-one
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Indoles
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Isoquinolines
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Ligands
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Receptors, Serotonin
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Serotonin 5-HT1 Receptor Agonists
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Serotonin 5-HT1 Receptor Antagonists
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Serotonin Antagonists
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Serotonin Receptor Agonists
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serotonin 7 receptor
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Receptor, Serotonin, 5-HT1A