3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships.
A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.
Nilsson
B M
BM
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, Sweden.
Sundquist
S
S
Johansson
G
G
Nordvall
G
G
Glas
G
G
Nilvebrant
L
L
Hacksell
U
U
D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism; D004563:Electrochemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D010306:Parotid Gland / Q000378:metabolism; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000378:metabolism
D018727:Muscarinic Antagonists; D011812:Quinuclidines