Bioorganic & Medicinal Chemistry Letters 20 (2010) 418–421
Bioorganic & Medicinal Chemistry Letters
Highly selective and potent
on morphine skeleton
l opioid ligands by unexpected substituent
Wei Li a, , Yi-Min Tao b, , Yun Tang c, Xue-Jun Xu b, Jie Chen b, Wei Fu a, Xing-Hai Wang a, Bo Chao a,
b,
Wei Sheng a, Qiong Xie a, Zhui-Bai Qiu a, , Jing-Gen Liu
*
*
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
c School of Pharmacy, East China University of Science & Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Unexpected substituent on the well-known morphine skeleton is described to be account for highly
Received 10 April 2009
Revised 15 July 2009
Accepted 27 July 2009
Available online 29 July 2009
selective and potent
l
opioid ligands, which is strongly connected to substituted aromatic groups on this
omitted 8 -position.
a
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
l
Opioid agonists
Selective ligands
Oripavines
Thebaine (Fig. 1) is a naturally occurred alkaloid isolated from
opium. Though it bears much similar structure with morphine,
thebaine is inactive as analgesic with very low affinities to opioid
receptors.1 However, it could be converted to a variety of potent
narcotics2 (e.g., Buprenorphine, Oxycodone) widely used in clinic
through several organic transformations. And the Diels–Alder reac-
tion of thebaine with dienophiles is obviously the most valuable
one among these reactions, which leads to the discovery of extre-
mely highly active analgesics than morphine.3 And due to less
selective characters1 of these so-called oripavines yielded from
the transformations of thebaine, the tritiated form of Diprenor-
phine and Etorphine has been used universally for opioid
receptors.
It is widely accepted that subtle differences in critical structural
loci of bioactive compounds may result in great changes in biolog-
ical responses. And these may provide useful information on drug-
receptor interactions and on receptor characteristics.4 Since the
greatly enhanced biological activities were suggested strongly to
be linked with the substituent on C7 position which may be
accommodated at the postulated lipophilic domain on the opioid
receptor,5 it was desirable to investigate other cycloadducts of the-
experimentally and theoretically.6 However, the 8
a-adducts have
been not considered seriously because not only are they not acces-
sible through the cycloaddition of thebaine and dienophiles to
date, but also significant decrease in analgesic potency7 and
reduced affinities8 to opioid receptors have been observed in the
known analogue in comparison to their main 7a-counterparts.
In this Letter we reported unexpected 8 -adducts yielded from
a
thebaine and styrenes which bear obviously different SARs (Struc-
ture–Activity Relationships) with other oripavines. And the substi-
tuent on the C8-position is strongly linked with
l opioid agonistic
activity and selectivity which has been omitted before.
A straightforward synthetic strategy was developed (Scheme 1),
and thebaine was preferably attacked by styrenes from the less
bulky b face9 to afford 6
a, 14a-endo-ethenotetrahydrothebaine.
In addition to known 7a-adducts yielded as main products, unex-
pected by-products were separated in case of styrene, m-nitrosty-
rene and p-nitrostyrene. Follow-up works examined compound-5
by X-ray crystallography (Fig. 2, compound-5, CCDC 696689) and
found it was a regioisomeric 8a-adduct in comparison to its main
7a-adduct (compound-4, CCDC 696688). Similar large deshielding
effect to the proximity of the tertiary amine is observed for H-8b in
1H NMR spectra of all regioisomeric adducts, as well as character-
istic resonances of H7b upfield due to absence of substitution
(Table 1). And normal 7b-adducts as were absent (Table 1).
In the absence of the polarizing methoxy functionality at C-6 of
thebaine, Diels–Alder addition to 3-buten-2-one can give a regio-
isomeric adduct in which the acetyl group is attached at C-8.7
And the Diels–Alder addition to styrenes may afford similar
baine with dienophiles besides the well investigated 7a-adducts
* Corresponding authors. Tel.: +86 21 54237595; fax: +86 21 54237264 (Z.-B.Q.);
tel.: +86 21 50807588 (J.-G.L.).
Liu).
Both authors contribute equally to this work.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.