SAR and biological evaluation of 3-azabicyclo[3.1.0]hexane derivatives as μ opioid ligands

3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral μ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity,...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-03, Vol.22 (6), p.2200-2203
Hauptverfasser:	Lunn, Graham, Roberts, Lee R., Content, Stephane, Critcher, Douglas J., Douglas, Sara, Fenwick, Ashley E., Gethin, David M., Goodwin, Graham, Greenway, David, Greenwood, Sean, Hall, Kim, Thomas, Martin, Thompson, Stephen, Williams, David, Wood, Gavin, Wylie, Andrew
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antipruritics - chemical synthesis Antipruritics - pharmacology binding capacity Biological and medical sciences Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis Bridged Bicyclo Compounds, Heterocyclic - pharmacology chemistry Dogs Guinea Pigs hexane Hexanes - chemical synthesis Hexanes - pharmacology Humans In Vitro Techniques Kinetics Ligands Medical sciences Opioid Pharmacology. Drug treatments pruritus Pruritus - drug therapy Pruritus - metabolism Receptors, Opioid, delta - antagonists & inhibitors Receptors, Opioid, delta - metabolism Receptors, Opioid, kappa - antagonists & inhibitors Receptors, Opioid, kappa - metabolism Receptors, Opioid, mu - antagonists & inhibitors Receptors, Opioid, mu - metabolism Structure-Activity Relationship μ Opioid
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Zusammenfassung:	3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral μ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the μ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described. 3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral μ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the μ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.01.099