Bioorganic & Medicinal Chemistry Letters
Narrow SAR in odorant sensing Orco receptor agonists
Ian M. Romaine a, Robert W. Taylor d, , Samsudeen P. Saidu d, Kwangho Kim a,b, Gary A. Sulikowski a,b
,
Laurence J. Zwiebel a,c,d, Alex G. Waterson a,b,c,
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a Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37322, United States
b Department of Chemistry, Vanderbilt University, Nashville, TN 37322, United States
c Department of Pharmacology, Vanderbilt University, Nashville, TN 37322, United States
d Department of Biological Sciences, Vanderbilt University, Nashville, TN 37322, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant
receptor is reported. The structure–activity relationships of independent sections of the molecules are
examined. Very small changes to the compound structure were found to exert a large impact on com-
pound activity. Optimal substitutions were combined using a ‘mix-and-match’ strategy to produce
best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form
the basis for the identification of a new mode of insect behavior modification.
Received 6 March 2014
Revised 18 April 2014
Accepted 21 April 2014
Available online 29 April 2014
Keywords:
Odorant receptor
VUAA1
Ó 2014 Elsevier Ltd. All rights reserved.
Structure activity relationship
Drosophila melanogaster
Insect chemosensory receptors from the odorant receptor (OR)
superfamily are responsible for a large portion of the peripheral
signal transduction that is required for the detection of a wide
array of volatile odorant compounds that exist in an insect’s envi-
ronment.1 In contrast to their mammalian counterparts, which are
G-protein coupled receptors, insect ORs act as heteromeric ligand
(odorant)-gated cation channels consisting of two 7-transmem-
brane domain protein subunits: the obligate OR co-receptor (Orco)
and an odorant-interacting ‘tuning’ OR (ORx).2–5 While Orco is
highly conserved across insect taxa, the tuning ORs tend to be
highly divergent and, for the most part, specific to individual insect
species.6 Recognition of an odorant ligand by the tuning OR is
thought to open the non-selective channel complex, which initi-
ates action potentials in odorant receptor neurons (ORNs), leading
to downstream neuronal activity that allows an insect to sample
and respond to its chemical environment.4,7 As many aspects of
insect behavior are directed on the basis of these olfactory pro-
cesses, adversely affecting or otherwise modulating the ability of
an insect to correctly sense and interpret environmental cues rep-
resents an established method of altering behavior to reduce the
impact of a wide range of economically and medically important
insect pests and disease vectors.
We have previously reported the identification and character-
ization of VUAA1 as an agonist of Orco action.8–10 Similar indepen-
dent efforts have identified additional active analogs in this
compound class.13–14 We have previously reported that more
potent analogs from the same chemical class are capable of affect-
ing the behavior of mosquito larvae in mobility assays at concen-
trations similar to, or lower than, those required for VUAA1
activity.11 Thus, we have continued to seek more potent analogs
of VUAA1 that would be capable of agonizing the ion channel at
more therapeutically useful doses. Here, we report the full details
of the structure–activity relationships (SAR) in the VUAA1 series
that led to the identification of more potent analogs. We have per-
formed a systematic evaluation of each section of the chemical
template and have noted that only an extremely narrow group of
substitutions leads to agonist activity. Following this initial survey,
a ‘mix and match’ strategy was undertaken to produce potent
compounds.
The VUAA1-based agonists were assembled using a straightfor-
ward and flexible synthetic route (Scheme 1). The route begins
with commercially available hydrazides (2), which were reacted
with isothiocyanates and then subsequently cyclized to generate
3-thio-1,2,4-triazoles (3). If necessary, carboxylic acid esters (1)
were first converted to the hydrazides. To construct the final ana-
logs, the thiols (3) were alkylated in a two-stage process beginning
with the condensation of anilines (4) with chloroacetyl chloride.
The resulting crude intermediate was reacted with the thiol to gen-
erate the agonists (5).
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Corresponding author. Tel.: +1 615 322 9971; fax: +1 615 875 3236.
Current address: Lurie Children’s Hospital Research Center, Chicago, IL 60614,
United States.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.