Synthesis and nicotinic binding of novel phenyl derivatives of UB-165. Identifying factors associated with α7 selectivity

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 17; pp. 2825 - 2828
• Main Authors: Karig, Gunter, Large, Jonathan M., Sharples, Christopher G.V., Sutherland, Andrew, Gallagher, Timothy, Wonnacott, Susan
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2003; Elsevier
• Subjects: Biological and medical sciences; Cholinergic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Nitrogen heterocycle; Ligand; Central nervous system; Selectivity; In vitro; Pyridine derivatives; Racemic; Alkaloid; Biological fixation; Cholinergic receptor; Position isomer; Structure activity relation; α7 nicotinic receptor; Bicyclic compound; Affinity; Benzenic compound; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00594-8

Four racemic phenyl-substituted analogues 3– 6 of the potent nicotinic agonist UB-165 1 have been synthesised and evaluated against the α 4β 2, α 3β 4, and α 7 neuronal nicotinic receptors. The 2′-phenyl derivative 3 shows no activity at these major receptor subtypes, while the 4′-phenyl analogue 4 shows an enhanced level of α 7 selectivity as compared to UB-165 and deschloro UB-165 2. These results are discussed within the context of recent pharmacophore models. Four phenyl substituted analogues of UB-165 have been synthesised and evaluated as nicotinic ligands. The 2′-phenyl derivative shows no activity at these major receptor subtypes, while the 4′-phenyl analogue shows an enhanced level of α 7 selectivity.