The treatment of airway obstructive disease may be improved by antimus
carinic agents which selectively block M(1) and M(3) receptors but do
not inhibit prejunctional cholinergic autoreceptors which limit releas
e of acetylcholine. Revatropate is a novel antimuscarinic agent which
shows some 50-fold selectivity for M(1) and M(3) receptors in guinea p
ig trachea and rabbit vas deferens over the M(2) subtype in atria. Thi
s selectivity profile was seen in vivo in anaesthetised guinea pigs an
d conscious dogs where bronchodilator activity was produced in the abs
ence of any effect on heart rate. Revatropate, in contrast to the non-
selective agent ipratropium, did not potentiate bronchoconstrictor res
ponses induced by vagal nerve stimulation, indicating that inhibitory
autoreceptors were still functional. Early clinical studies in COAD pa
tients showed that inhaled revatropate was an effective bronchodilator
which was well tolerated. Darifenacin differs from revatropate by sho
wing selectivity for M(3) receptors relative to both M(2) and M(1) sub
types. [H-3] darifenacin had 5-fold higher affinity for the human m3 r
elative to m1 receptors while there was significantly reduced binding
to m2, m4 and m5 receptors. The degree of selectivity in functional ti
ssue preparations was even greater, with darifenacin showing 100-fold
selectivity for the ileum M(3) receptors over M(2) receptors in atria
and 30-fold over M(1) receptors in rabbit vas deferens. Darifenacin wa
s able to differentiate between M(3) receptors in different tissues; a
lthough darifenacin was equipotent with atropine in the ileum and blad
der, it was some 10-fold and 6-fold less potent at inhibiting muscarin
ic responses in the trachea and submandibular salivary gland respectiv
ely, relative to atropine. Studies in anaesthetised dogs confirmed thi
s selectivity profile. Thus darifenacin inhibited responses of the gut
and bladder to cholinergic stimulation without affecting heart rate.
Salivary gland responses were inhibited at doses some 6-10 fold higher
than those required to inhibit gut and bladder responses. Clinical st
udies are ongoing in urge incontinence and functional bowel disease wh
ich may confirm this selectivity profile.