Transient
receptor potential melastatin 8 (TRPM8) ion channel represents
a valuable pharmacological option for several therapeutic areas. Here,
a series of conformationally restricted derivatives of the previously
described TRPM8 antagonist
N
,
N
′-dibenzyl
tryptophan
4
were prepared and characterized in vitro
by Ca
2+
-imaging and patch-clamp electrophysiology assays.
Molecular modeling studies led to identification of a broad and well-defined
interaction network of these derivatives inside the TRPM8 binding
site, underlying their antagonist activity. The (5
R
,11a
S
)-5-(4-chlorophenyl)-2-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1
H
-imidazo[1′,5′:1,6]pyrido[3,4-
b
]indole-1,3(2
H
)-dione (
31a
) emerged as a potent (IC
50
= 4.10 ± 1.2 nM), selective,
and metabolically stable TRPM8 antagonist. In vivo,
31a
showed significant target coverage in an icilin-induced WDS (at
11.5 mg/kg ip), an oxaliplatin-induced cold allodynia (at 10–30
μg sc), and CCI-induced thermal hyperalgesia (at 11.5 mg/kg
ip) mice models. These results confirm the tryptophan moiety as a
solid pharmacophore template for the design of highly potent modulators
of TRPM8-mediated activities.