Abstract
A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC(50) of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.
© 2012 American Chemical Society
MeSH terms
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Adrenergic Uptake Inhibitors / chemical synthesis*
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Adrenergic Uptake Inhibitors / chemistry
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Adrenergic Uptake Inhibitors / pharmacology
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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CHO Cells
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Coronary Vessels / drug effects
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Coronary Vessels / physiology
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Cricetinae
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Cricetulus
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Cyclohexanes / chemical synthesis
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Cyclohexanes / chemistry
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Cyclohexanes / pharmacology
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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HEK293 Cells
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High-Throughput Screening Assays
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Humans
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Muscle Contraction
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / physiology
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Neuralgia / drug therapy*
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Nitric Oxide Synthase Type I / antagonists & inhibitors*
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Norepinephrine Plasma Membrane Transport Proteins / metabolism*
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Vascular Resistance
Substances
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Adrenergic Uptake Inhibitors
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Analgesics
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Cyclohexanes
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Indoles
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N-(3-(3-(methylamino)cyclohexyl)-1H-indol-5-yl)thiophene-2-carboximidamide
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Norepinephrine Plasma Membrane Transport Proteins
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Thiophenes
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Nitric Oxide Synthase Type I