Bioorganic & Medicinal Chemistry Letters 17 (2007) 1508–1511
High-affinity carbamate analogues of morphinan at opioid receptors
Xuemei Peng,a Brian I. Knapp,b Jean M. Bidlackb and John L. Neumeyera,*
aAlcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
bDepartment of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
Received 21 November 2006; revised 1 January 2007; accepted 3 January 2007
Available online 17 January 2007
Abstract—A series of carbamate analogues were synthesized from levorphanol (1a), cyclorphan (2a) or butorphan (3a) and evalu-
ated in vitro for their binding affinity at l, d, and j opioid receptors. Functional activities of these compounds were measured in the
[35S]GTPcS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for j receptor (Ki = 0.046 and
0.051 nM) and for l receptor (Ki = 0.11 and 0.12 nM). Compound 1c showed the highest l selectivity. The preliminary assay for
agonist and antagonist properties of these ligands in stimulating [35S]GTPcS binding mediated by the j opioid receptor illustrated
that all of these ligands were j agonists. At the l receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c–e and
3c–e were l agonists/antagonists.
Ó 2007 Elsevier Ltd. All rights reserved.
Treatment of severe pain often requires use of opioid
analgesics such as morphine, their use is limited by seri-
ous side-effects including tolerance, physical depen-
dence, respiratory depression, and addiction liability.
Numerous opiates have been synthesized in an effort
to obtain analgesics that are free of such side effects.1
which is also a potential site for metabolism, conjuga-
tion, and excretion via O-glucuronidation resulting in
low oral bioavailability and short duration of action.1
An approach to improving the pharmacological proper-
ties of analgesics such as morphine is to modify the phe-
nolic hydroxy function.
Opioids bind to specific neuronally located proteins
which initiate biologic responses. Opioid receptors were
first discovered in mammalian brain and belong to the
rhodopsin subfamily in the superfamily of over 1000 G
protein-coupled receptors.2 Three opioid receptor types,
kappa (j), delta (d), and mu (l),3–5 differ in their distri-
bution and ligand binding, and were identified through
pharmacological and physiological studies using selec-
tive ligands.
To develop additional insight into the SAR surrounding
the 3-position of morphinan, we wished to modify the
3-OH function of morphinan. The carbamate group
was introduced because it is a structure of medium
polarity, capable of forming hydrogen bonds as donor
and acceptor.7–9 Ideally, these modified compounds
would have a longer duration of action and better bio-
availability. We report a series of morphinans where
the 3-OH was modified by incorporating the carbamate
function at the 3-position of the morphinan template.
By the synthesis of a series of carbamate analogues of
morphinans and evaluation of their binding affinities
at opioid receptors, our objective is to identify long-act-
ing opioid receptor ligands useful for the treatment of
cocaine abuse. Earlier studies have shown that the basic
nitrogen and a phenol moiety were necessary for narcot-
ic analgesics to bind to its opioid receptors.6 As is the
case for morphine derivatives, the phenolic hydroxyl
group in morphinan contributes to analgesic activity,
The levorotatory morphinans (2a and 3a) were prepared
from commercially available (À)-3-hydroxy-N-meth-
ylmorphinan tartrate (levorphanol) 1a which was con-
verted to the free base and N-demethylated10–12 to
yield the normorphinan. Alkylation with cyclopropylm-
ethyl or cyclobutylmethyl bromide led to the (À)-N-
substituted morphinan characterized as their crystalline
mandelate salts (2a and 3a), respectively.
A series of carbamates were prepared using morphinans
(1a, 2a and 3a) as starting materials. The carbamates
were prepared in yields ranging from 55% to 90% by
treating the morphinans (1a, 2a and 3a) with the
Keywords: Morphinan; Carbamate; Opioid; Receptors.
*
Corresponding author. Tel.: +1 6178553388; fax: +1 6718552519;
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.013