First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain.

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.

• Authors: Gabriela Mladenova, Subhash C Annedi, Jailall Ramnauth, Shawn P Maddaford, Suman Rakhit, John S Andrews, Dongqin Zhang, Frank Porreca
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 7 Pg. 3488-501 (Apr 12 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22420844 (Publication Type: Journal Article)
• Copyright: © 2012 American Chemical Society

Chemical References

• Adrenergic Uptake Inhibitors
• Analgesics
• Cyclohexanes
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• Indoles
• N-(3-(3-(methylamino)cyclohexyl)-1H-indol-5-yl)thiophene-2-carboximidamide
• Norepinephrine Plasma Membrane Transport Proteins
• Thiophenes
• Nitric Oxide Synthase Type I

Topics

• Adrenergic Uptake Inhibitors (chemical synthesis, chemistry, pharmacology)
• Analgesics (chemical synthesis, chemistry, pharmacology)
• Animals
• CHO Cells
• Coronary Vessels (drug effects, physiology)
• Cricetinae
• Cricetulus
• Cyclohexanes (chemical synthesis, chemistry, pharmacology)
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• HEK293 Cells
• High-Throughput Screening Assays
• Humans
• In Vitro Techniques
• Indoles (chemical synthesis, chemistry, pharmacology)
• Muscle Contraction
• Muscle, Smooth, Vascular (drug effects, physiology)
• Neuralgia (drug therapy)
• Nitric Oxide Synthase Type I (antagonists & inhibitors)
• Norepinephrine Plasma Membrane Transport Proteins (metabolism)
• Rats
• Stereoisomerism
• Structure-Activity Relationship
• Thiophenes (chemical synthesis, chemistry, pharmacology)
• Vascular Resistance