Abstract
A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.
MeSH terms
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Duodenum / drug effects
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Duodenum / physiology
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Humans
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In Vitro Techniques
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Macrocyclic Compounds / chemical synthesis*
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology
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Molecular Mimicry
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Muscle Contraction / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Rabbits
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Radioligand Assay
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Receptors, Gastrointestinal Hormone / antagonists & inhibitors*
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Receptors, Neuropeptide / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Macrocyclic Compounds
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Oligopeptides
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Receptors, Gastrointestinal Hormone
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Receptors, Neuropeptide
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motilin receptor