Abstract
Neurotensin receptor type 2 (NTS2) compounds display analgesic activity in animal pain models. We have identified the first high-affinity NTS2-selective antagonist (8) that is active in vivo. This study also revealed that the NTS2 FLIPR assay designation for a compound, agonist, partial agonist, and so forth, did not correlate with its in vivo activity as observed in the thermal tail-flick acute model of pain. This suggests that calcium mobilization is not the signaling pathway involved in NTS2-mediated analgesia as assessed by the thermal tail-flick model. Finally, we found a significant bias between rat and human for compound 9 in the NTS2 binding assay.
Keywords:
FLIPR assay; NT79; NTRC-844; NTS2 receptor; Neurotensin; analgesia; thermal tail-flick.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / pharmacology
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Analgesics / therapeutic use*
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Analysis of Variance
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Animals
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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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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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Calcium / metabolism
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Carboxylic Acids / chemistry*
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Hindlimb Suspension
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Humans
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Injections, Spinal
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Male
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Neurotransmitter Agents / chemical synthesis
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Neurotransmitter Agents / chemistry
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Neurotransmitter Agents / pharmacology*
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Pain / drug therapy*
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Pain / physiopathology
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Piperidines / chemistry*
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Protein Binding / drug effects
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrazoles / therapeutic use
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Reaction Time / drug effects
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Receptors, Neurotensin / antagonists & inhibitors*
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Receptors, Neurotensin / metabolism*
Substances
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Analgesics
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Bridged Bicyclo Compounds, Heterocyclic
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Carboxylic Acids
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NTRC-844
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Neurotransmitter Agents
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Piperidines
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Pyrazoles
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Receptors, Neurotensin
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Calcium