Structure-Affinity Relationship Study of Novel Imidazoline Ligands at Imidazoline Binding Sites and α-Adrenoceptors

• Author / Creator

  Ferdousi, Mehnaz I

• Many drugs containing an imidazoline moiety are thought to bind to both imidazoline binding sites (IBS) and α-adrenoceptors (α-AR) to mediate their therapeutic effects. To aid in better characterisation of these binding sites, the structure-affinity relationships of several new series of imidazoline containing ligands with regard to activity at α-AR and IBS were explored in this project. Radioligand binding was used to investigate the affinity and selectivity of these ligands for similar receptor types, α1- and α2-AR and I1- and I2BS, in rat whole brain and kidney membranes. In an MP series of compounds, the minor structural modifications investigated in this study appeared to favour I2BS selectivity in general. Additionally substituents with low steric bulk (like chloro and methyl) at ortho position of the aromatic ring in MP compounds maintained affinity and selectivity at corresponding receptive sites. Similar observation was made with compounds (derivatives of marsanidine, a selective partial α2-AR agonist) in TCS/TCA series where halogen and methyl substitutions were well tolerated with respect to α2-AR affinity, although these ligands were nonselective in nature. Among the compounds of AW series (fluorinated derivatives of marsanidine and its heteroarylmethyl analogue), AW-21 with fluorine substituted at C-7 on the heteroaromatic ring displayed high nanomolar affinity and selectivity for α2-AR versus other receptor types. Further in vivo assessment using brain microdialysis showed that AW-21, when administered intraperitoneally, reduced extracellular noradrenaline levels in rat frontal cortex in a dose related manner. Moreover, AW-21 rapidly induced sedation in rats following systemic administration indicating that it can cross the blood-brain barrier. Taken together, preliminary data suggests that AW-21 possesses favourable binding and pharmacological profiles, indicating its potential to be a suitable candidate for selective α2-AR positron emission tomography (PET) ligand.

• Subjects / Keywords

  • Positron emission tomography
  • Alpha-2 adrenoceptors
  • Depression
  • Imidazoline binding sites
  • Affinity and selectivity

• Graduation date

  Fall 2014

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R32B8VH6X

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.