Bioorganic & Medicinal Chemistry Letters
Development of indole sulfonamides as cannabinoid receptor
negative allosteric modulators
Iain R. Greig a, , Gemma L. Baillie a,b, Mostafa Abdelrahman c,d, Laurent Trembleau c, Ruth A. Ross a,b
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a Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
b Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto,
Ontario M5S 1A8, Canada
c Laboratory of Supramolecular Chemistry, School of Natural and Computing Sciences, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK
d Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite
of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to
demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molec-
ular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this
study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of
4 and 3 nM respectively, and showed good oral exposure and CNS penetration, making them highly ver-
satile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
Crown Copyright Ó 2016 Published by Elsevier Ltd. All rights reserved.
Received 14 July 2016
Revised 5 August 2016
Accepted 6 August 2016
Available online xxxx
Keywords:
Cannabinoid
Negative allosteric modulator
CB1 NAM
Indole sulfonamide
Drugs which block cannabinoid receptor activation were
expected to find a huge market for the treatment of obesity, addic-
tion and metabolic syndromes (e.g. type-2 diabetes). However,
rejection by the FDA and eventual withdrawal in Europe of the first
such drug to reach the market (rimonabant) effectively terminated
this line of approach, in spite of the apparent therapeutic utility.1
There are a number of different approaches now being taken to
harness the potential of the cannabinoid system, whilst avoiding
the side-effects of previous approaches that entailed global antag-
onism.2 Such approaches include the use of neutral antagonists,
negative allosteric modulators and peripheral restriction.1,2
peripheral CB1 receptors on the modulation of metabolism and
the potential for therapeutic benefit in the absence of CNS-medi-
ated side-effects.1
Allosteric modulators are playing an increasingly prominent
role in therapeutics, having the advantage of more subtle modula-
tion of receptor activity than intervention at the orthosteric site,
the normal binding site for the endogenous ligand. Furthermore,
the allosteric sites of many receptors offer greater opportunities
for selectivity, whereas the orthosteric sites of many receptors
and subtypes can be too similar to allow a drug to distinguish
between them, as they often must bind the same endogenous
ligand.8 In 2005, the first evidence was published indicating that
the cannabinoid CB1 receptor contains an allosteric binding site
and compounds such as Org27569 were identified that unexpect-
edly were allosteric enhancers of agonist binding affinity, but func-
tionally were allosteric inhibitors of agonist signalling efficacy.9
Related analogues of Org2756910–14 and the diphenylurea
PSNCBAM-115 were subsequently found to display similar pharma-
cological profiles. Org27569 and analogues have been widely stud-
ied and photo-activated derivatives of Org27569 have been highly
effective for mapping of the CB1 allosteric binding site.16,17 How-
ever, in vivo studies using Org27569 gave unexpected results:
Org27569 did not modulate agonist-induced catalepsy or nocicep-
tion,18,19 though it did antagonize reinstatement of extinguished
cocaine and methamphetamine seeking behaviours,20 and showed
conflicting effects on agonist-induced hypothermia.18,19 Thus, both
CB1 receptors and endocannabinoids are present in peripheral
tissues involved in metabolic dysfunction associated with obesity,
including adipose tissue, liver, skeletal muscle and pancreas, and
there is evidence for the upregulation of the endocannabinoid sys-
tem in these tissues in experimental and human obesity.3 Activa-
tion of CB1 receptors in peripheral tissues promotes lipogenesis,
lipid storage, insulin secretion, glucagon secretion and adiponectin
modulation.4–6 Furthermore, a peripherally-restricted CB1 receptor
antagonist does not affect behavioural responses in mice with
genetic or diet-induced obesity, but it does cause weight-indepen-
dent improvements in glucose homeostasis, fatty liver, and plasma
lipid profile.7 These findings confirm
a prominent role for
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Corresponding author. Tel.: +44 1224 437370.
0960-894X/Crown Copyright Ó 2016 Published by Elsevier Ltd. All rights reserved.