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The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol.
Neuropharmacology. 2008 Feb; 54(2):331-43.N

Abstract

Tramadol is an atypical analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of noradrenaline (NA) and serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at micro-opioid receptors. Here, we present data for the novel compound NS7051, which was shown to have sub-micromolar affinity (Ki=0.034microM) for micro-opioid receptors and inhibited reuptake of 5-HT, NA and DA (IC(50)=4.2, 3.3 and 3.5microM in cortex, hippocampus and striatum respectively). NS7051 (1-30mg/kg, s.c.) produced a dose-dependent naloxone-reversible increase in the hot plate withdrawal latency, and was also analgesic in the tail flick test. In models of persistent and chronic inflammatory nociception, NS7051 reversed flinching behaviours during interphase and second phase of the formalin test (ED(50)=1.7 and 1.8mg/kg, s.c.), and hindpaw weight-bearing deficits induced by complete Freund's adjuvant injection (ED50=1.2mg/kg, s.c.). In the chronic constriction injury model of neuropathic pain, mechanical allodynia and hyperalgesia were both reversed by NS7051 (ED50=6.7 and 4.9mg/kg, s.c.). Tramadol was also active in all pain models although at considerably higher doses (20-160mg/kg, s.c.). No ataxia was observed at antiallodynic doses giving therapeutic indices of 19 and 3 for NS7051 and tramadol. The combined opioid receptor agonism and monoamine reuptake inhibitory properties of NS7051 inferred from behavioural studies appear to contribute to its well tolerated antinociceptive profile in rats. However, unlike tramadol this did not correlate with the ability to increase hippocampal monoamine levels measured by microdialysis in anesthetised rats.

Authors+Show Affiliations

NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark. gmu@neurosearch.dkNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

18037451

Citation

Munro, Gordon, et al. "The Novel Compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) Attenuates Nociceptive Transmission in Animal Models of Experimental Pain; a Pharmacological Comparison With the Combined Mu-opioid Receptor Agonist and Monoamine Reuptake Inhibitor Tramadol." Neuropharmacology, vol. 54, no. 2, 2008, pp. 331-43.
Munro G, Baek CA, Erichsen HK, et al. The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol. Neuropharmacology. 2008;54(2):331-43.
Munro, G., Baek, C. A., Erichsen, H. K., Nielsen, A. N., Nielsen, E. Ø., Scheel-Kruger, J., Weikop, P., & Peters, D. (2008). The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol. Neuropharmacology, 54(2), 331-43.
Munro G, et al. The Novel Compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) Attenuates Nociceptive Transmission in Animal Models of Experimental Pain; a Pharmacological Comparison With the Combined Mu-opioid Receptor Agonist and Monoamine Reuptake Inhibitor Tramadol. Neuropharmacology. 2008;54(2):331-43. PubMed PMID: 18037451.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol. AU - Munro,Gordon, AU - Baek,Camilla A E, AU - Erichsen,Helle K, AU - Nielsen,Alexander N, AU - Nielsen,Elsebet Ø, AU - Scheel-Kruger,Jørgen, AU - Weikop,Pia, AU - Peters,Dan, Y1 - 2007/10/16/ PY - 2007/08/20/received PY - 2007/10/05/revised PY - 2007/10/05/accepted PY - 2007/11/27/pubmed PY - 2008/5/13/medline PY - 2007/11/27/entrez SP - 331 EP - 43 JF - Neuropharmacology JO - Neuropharmacology VL - 54 IS - 2 N2 - Tramadol is an atypical analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of noradrenaline (NA) and serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at micro-opioid receptors. Here, we present data for the novel compound NS7051, which was shown to have sub-micromolar affinity (Ki=0.034microM) for micro-opioid receptors and inhibited reuptake of 5-HT, NA and DA (IC(50)=4.2, 3.3 and 3.5microM in cortex, hippocampus and striatum respectively). NS7051 (1-30mg/kg, s.c.) produced a dose-dependent naloxone-reversible increase in the hot plate withdrawal latency, and was also analgesic in the tail flick test. In models of persistent and chronic inflammatory nociception, NS7051 reversed flinching behaviours during interphase and second phase of the formalin test (ED(50)=1.7 and 1.8mg/kg, s.c.), and hindpaw weight-bearing deficits induced by complete Freund's adjuvant injection (ED50=1.2mg/kg, s.c.). In the chronic constriction injury model of neuropathic pain, mechanical allodynia and hyperalgesia were both reversed by NS7051 (ED50=6.7 and 4.9mg/kg, s.c.). Tramadol was also active in all pain models although at considerably higher doses (20-160mg/kg, s.c.). No ataxia was observed at antiallodynic doses giving therapeutic indices of 19 and 3 for NS7051 and tramadol. The combined opioid receptor agonism and monoamine reuptake inhibitory properties of NS7051 inferred from behavioural studies appear to contribute to its well tolerated antinociceptive profile in rats. However, unlike tramadol this did not correlate with the ability to increase hippocampal monoamine levels measured by microdialysis in anesthetised rats. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/18037451/The_novel_compound__+/___1_[10___E__3_Phenyl_allyl__310_diaza_bicyclo[4_3_1]dec_3_yl]_propan_1_one__NS7051__attenuates_nociceptive_transmission_in_animal_models_of_experimental_pain L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(07)00324-3 DB - PRIME DP - Unbound Medicine ER -