PMID- 22420844
OWN - NLM
STAT- MEDLINE
DCOM- 20120831
LR  - 20161125
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 55
IP  - 7
DP  - 2012 Apr 12
TI  - 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.
PG  - 3488-501
LID - 10.1021/jm300138g [doi]
AB  - 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 muM, 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.
CI  - (c) 2012 American Chemical Society
FAU - Mladenova, Gabriela
AU  - Mladenova G
AD  - NeurAxon Inc., 2395 Speakman Drive, Suite 1001, Mississauga, Ontario L5K 1B3, 
      Canada. gmladenova@neuraxon.com
FAU - Annedi, Subhash C
AU  - Annedi SC
FAU - Ramnauth, Jailall
AU  - Ramnauth J
FAU - Maddaford, Shawn P
AU  - Maddaford SP
FAU - Rakhit, Suman
AU  - Rakhit S
FAU - Andrews, John S
AU  - Andrews JS
FAU - Zhang, Dongqin
AU  - Zhang D
FAU - Porreca, Frank
AU  - Porreca F
LA  - eng
PT  - Journal Article
DEP - 20120404
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Adrenergic Uptake Inhibitors)
RN  - 0 (Analgesics)
RN  - 0 (Cyclohexanes)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (Indoles)
RN  - 0 (N-(3-(3-(methylamino)cyclohexyl)-1H-indol-5-yl)thiophene-2-carboximidamide)
RN  - 0 (Norepinephrine Plasma Membrane Transport Proteins)
RN  - 0 (Thiophenes)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
SB  - IM
MH  - Adrenergic Uptake Inhibitors/*chemical synthesis/chemistry/pharmacology
MH  - Analgesics/*chemical synthesis/chemistry/pharmacology
MH  - Animals
MH  - CHO Cells
MH  - Coronary Vessels/drug effects/physiology
MH  - Cricetinae
MH  - Cricetulus
MH  - Cyclohexanes/chemical synthesis/chemistry/pharmacology
MH  - ERG1 Potassium Channel
MH  - Ether-A-Go-Go Potassium Channels/antagonists & inhibitors
MH  - HEK293 Cells
MH  - High-Throughput Screening Assays
MH  - Humans
MH  - In Vitro Techniques
MH  - Indoles/*chemical synthesis/chemistry/pharmacology
MH  - Muscle Contraction
MH  - Muscle, Smooth, Vascular/drug effects/physiology
MH  - Neuralgia/*drug therapy
MH  - Nitric Oxide Synthase Type I/*antagonists & inhibitors
MH  - Norepinephrine Plasma Membrane Transport Proteins/*metabolism
MH  - Rats
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Thiophenes/*chemical synthesis/chemistry/pharmacology
MH  - Vascular Resistance
EDAT- 2012/03/17 06:00
MHDA- 2012/09/01 06:00
CRDT- 2012/03/17 06:00
PHST- 2012/03/17 06:00 [entrez]
PHST- 2012/03/17 06:00 [pubmed]
PHST- 2012/09/01 06:00 [medline]
AID - 10.1021/jm300138g [doi]
PST - ppublish
SO  - J Med Chem. 2012 Apr 12;55(7):3488-501. doi: 10.1021/jm300138g. Epub 2012 Apr 4.