title: 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.affiliation: NeurAxon Inc., 2395 Speakman Drive, Suite 1001, Mississauga, Ontario L5K 1B3, Canada. gmladenova@neuraxon.com
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mladenova
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Annedi
authors.forename: Jailall
authors.initials: J
authors.lastname: Ramnauth
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Maddaford
authors.forename: Suman
authors.initials: S
authors.lastname: Rakhit
authors.forename: John S
authors.initials: JS
authors.lastname: Andrews
authors.forename: Dongqin
authors.initials: D
authors.lastname: Zhang
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014655:Vascular Resistance
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000700:Analgesics; D003510:Cyclohexanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; C574652:N-(3-(3-(methylamino)cyclohexyl)-1H-indol-5-yl)thiophene-2-carboximidamide; D050484:Norepinephrine Plasma Membrane Transport Proteins; D013876:Thiophenes; D052248:Nitric Oxide Synthase Type I