jm970346t_si_001.pdf (767.7 kB)
Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene Derivatives: Synthesis and Structure−Activity Relationships
journal contribution
posted on 1997-11-07, 00:00 authored by Gary Johansson, Staffan Sundquist, Gunnar Nordvall, Björn M. Nilsson, Magnus Brisander, Lisbeth Nilvebrant, Uli HacksellA series of 25 derivatives of the muscarinic antagonist
3-(2-furanyl)quinuclidin-2-ene (4) was
synthesized and evaluated for muscarinic and antimuscarinic properties.
Substitution at all
three positions of the furan ring has been investigated. The
affinities of the new compounds
were determined by competition experiments in homogenates of cerebral
cortex, heart, parotid
gland, and urinary bladder from guinea pigs using
(−)-[3H]-3-quinuclidinyl benzilate as the
radioligand, and the antimuscarinic potency was determined in a
functional assay on isolated
guinea pig urinary bladder using carbachol as the agonist. Several
of the novel derivatives
displayed high muscarinic affinities. Whereas the affinity of lead
compound 4 for cortical
muscarinic receptors is moderate (Ki = 300
nM), it is much higher for the 5-methyl (48;
Ki =
12 nM), 5-ethyl (52; Ki = 7.4 nM),
5-bromo (33; Ki = 6.4 nM), and
3-phenyl (49; Ki = 2.8
nM)
substituted derivatives. The substituent-induced increases in
affinity do not appear to be
additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl
(55) substitution pattern only
slightly increases affinity (Ki = 1.55 and
2.39 nM, respectively). The conformational
preferences
of the 3-phenyl (49) and 5-phenyl (51)
derivatives were studied by X-ray crystallography and
molecular mechanics calculations. Because of the observed high
affinity of 49, a series of 16
meta- and para-substituted analogues of 49 was synthesized
and tested. The m-hydroxy
derivative (68) exhibited more than 10-fold improvement in
affinity as compared to 49. The
structure−activity relationships of the new series are well described
with QSAR and CoMFA
models.