Synthesis and evaluation of a full-agonist orvinol for PET-imaging of opioid receptors: [11C]PEO

Article abstract of DOI:10.1021/jm900892x

Antagonist radiotracers have shown only a low sensitivity for detecting competition from high-efficacy agonists at opioid receptors (ORs) in vivo. We report that [¹¹C]PEO binds with high affinity to μ and κ-opioid receptors, is a full agonist, and concentrates in brain regions of rats with a high density of the μ-OR after intravenous injection. Blocking studies with μ and κ-OR selective compounds demonstrated that the binding of [¹¹C]PEO is saturable and selective to the μ-OR in rat brain.

Full text of DOI:10.1021/jm900892x

5586 J. Med. Chem. 2009, 52, 5586–5589
DOI: 10.1021/jm900892x
spectrum of intrinsic activities at μ-OR among these com-
pounds (Chart 1).
Synthesis and Evaluation of a Full-Agonist
Orvinol for PET-Imaging of Opioid Receptors:
[11C]PEO
(20R)-4,5-R-Epoxy-17-methyl-3-hydroxy-6-methoxy-R,17-
dimethyl-R-(2-phenylethyl)-6,14-ethenomorphinan-7-metha-
nol (PEOa) belongs to theBentley compounds.14 Inthis paper,
we report the synthesis of [11C]PEO and the biological evalua-
tion of this compound as a potential PET tracer.
†
Janos Marton, Bent W. Schoultz, Trine Hjornevik,
Alexander Drzezga, Behrooz H. Yousefi,
Hans-Jurgen Wester, Frode Willoch,§,^ and
Gjermund Henriksen*, ,‡
‡
§
ꢀ
e
The TDPEO (6) precursor for radiolabeling was prepared
fromthebaine (1; CAS RN: [115-37-7]) ina five-step synthesis.
The synthesis of [6-O-methyl-11C]PEO ([11C]PEO, [11C]4) is
displayed in Scheme 1. In principle, the Diels-Alder (DA)
reaction of morphinan-6,8-dienes with unsymmetrical dieno-
philes can afford eight isomers: the 7R-, 7β-, 8R-, 8β-substi-
tuted 6R,14R-etheno in addition to the corresponding four
6β,14β-etheno analogues.15 The addition of methyl vinyl
ketone to the T-shaped thebaine (1) molecule is regio- and
stereoselective occurring on the β-face and gives exclusively
the C-7 acetyl derivatives. The regioselectivity is induced by
the 6-OCH3 moiety that polarizes the diene system.16-18 Thus
DA addition of methyl vinyl ketone to thebaine (1) resulted in
thevinone (2a; CAS RN: [15358-22-2]) as the main product
(81%) and β-thevinone (2b; CAS RN: [16196-83-1]) as by-
product.
The 7R-ketone (2a) was reacted with 2-phenylethylmagne-
sium bromide and gave a complex product mixture (3a, 3b, 3c,
and 3d). The reaction took place with a high degree of
stereoselectivity, in accordance with Cram’s rule,19 and resul-
tedinthe tertiary alcohol3a(CASRN:[13965-63-4]) with20R
absolute configuration as the main product (62%). The
formation of the major byproduct (3b) is the result of a
base-catalyzed rearrangement,20 which was followed by
Grignard addition. In the case of 2-phenylethylmagnesium
bromide, a β-hydrogen transfer is also possible (Grignard
reduction). A mixture of secondary alcohols 3c/3d was iso-
lated as minor byproducts(1.7%). Weconfirmedthestructure
of 3b by acid catalyzed dehydration, enol-ether hydrolysis,
and rearrangement20 to the 5,14-bridged thebainone deriva-
tive (7). 3-O-demethylation14 of (20R)-phenylethyl thevinol
(3a) resulted in (20R)-phenylethyl orvinol (PEO, 4; CAS RN:
[14521-98-3]), and the following 6-O-demethylation13 led to
6-O-desmethyl-PEO (DPEO, 5). 3-O-Tritylation of 5 in di-
chloromethane in the presence of triethylamine provided the
trityl-protected precursor (TDPEO, 6) for radiolabeling in
>99% purity.
† ABX Advanced Biochemical Compounds, Biomedizinische
Forschungsreagenzien GmbH, Radeberg, Germany, ‡ Department of
Chemistry, University of Oslo, PO Box 1033, Blindern N-0315 Oslo,
Norway, § Centre for Molecular Biology and Neuroscience & Institute
of Basic Medical Sciences, University of Oslo, PO Box 1105, Blindern
N-0317 Oslo, Norway, Department of Nuclear Medicine, Klinikum
Rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse
22, D-81675 Munich, Germany, and ^ Akershus University Hospital,
PO Box 300, N-1471 Lorenskog, Norway
e
Received June 18, 2009
Abstract: Antagonist radiotracers have shown only a low sensiti-
vity for detecting competition from high-efficacy agonists at opioid
receptors (ORs) in vivo. We report that [11C]PEO binds with high
affinity to μ and κ-opioid receptors, is a full agonist, and concen-
trates in brain regions of rats with a high density of the μ-OR after
intravenous injection. Blocking studies with μ and κ-OR selective
compounds demonstrated that the binding of [11C]PEO is saturable
and selective to the μ-OR in rat brain.
The μ-, δ-, and κ-opioid receptors1 are distributed in the
central nervous system (CNS) of mammals. These opioid
receptors (ORs) mediate the effects of the endogenous opioid
peptides and are known to be involved in several physiological
functions, includingpainmodulation2,3 aswell asrepresenting
molecular targets of opioid and several stimulant drugs of
abuse.4,5
NoninvasiveimagingofORsbymeans of positronemission
tomography (PET) enables investigations of the relationship
between OR-mediated signaling and (patho)physiology at the
molecular level.6 The nonselective OR-antagonists [6-O-
methyl-11C]diprenorphine ([11C]DPN) and [6-O-(2-[18F]fluoro-
ethyl)]- diprenorphine ([18F]FDPN) are currently employed
for studies in humans.7-10 Despite detectable changes in OR
occupancy of these orvinols in studies of chronic and experi-
mental pain, pharmacological studies in humans11 and rats12
have supported minimal competition between high-efficacy
agonists and [11C]DPN. This has led to the conclusion of a
limited utility of DPN for monitoring OR occupancy in vivo.
Even though the μ-OR agonist [11C]carfentanil is available
for PET studies,6 the employment of structurally matched
agonist/antagonist pairscouldsimplify a testof the hypothesis
whether an OR agonist PET tracer is more sensitive to
competition relative to one with antagonistic properties.
These investigations have so far been hampered by the lack
of available tracers. Buprenorphine, a μ-partial agonist and
κ-antagonist, is already available as the 11C-version13 and
could, upon availability of an agonist orvinol, complete the
The radiosynthesis of [11C]4 was accomplished by treating 6
with 8-10 equiv NaH in DMF, followed by reaction with
[11C]methyl iodide (5 min, 90 ꢀC) and removal of the trityl
group by adding 1 M HCl in EtOH. The crude product was
purified by HPLC, yielding [11C]4 in a decay-corrected radio-
chemical yield of 57 ( 16%, based on [11C]MeI (n=18), in a
specific activity of 1622 ( 233 mCi/μmol at end-of-synthesis
and in a chemical purity of >99%.
a Abbreviations: PEO, (20R)phenylethyl orvinol; DPEO, (20R)-6-O-
Desmethyl-phenylethyl orvinol = 6-O-Desmethyl-PEO; TDPEO, (20R)-3-
O-Trityl-6-O-desmethyl-phenylethyl orvinol; CHO, Chinese hamster ovary.
HEK, human embryonic kidney. GTPγS, guanosine-50-O-(3-thio)-tripho-
sphate. DAMGO, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; U69593,
(þ)-(5R,7R,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-
benzeneacetamide.
*To whom correspondence should be addressed. Phone: þ49 89 4140
2986. Fax: þ49 89 4140 4841. E-mail: G.Henriksen@lrz.tum.de.
r
pubs.acs.org/jmc
Published on Web 08/20/2009
2009 American Chemical Society

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 5587
The octanol-PBS partition coefficient (logPoct/PBS) of
1 nM concentration of the ligand in question. The high
potency of 4 found in the present work is consistent with the
original report on the high in vivo potency of this com-
pound.14 To determine the regional brain uptake kinetics of
[11C]4, male Wistar rats were injected intravenously (iv) with
the radiotracer and sacrificed at different time points after
injection. Dissected brain regions were measured for their
content of radioactivity. The results from this ex vivo biodis-
tribution study are listed in Table 1.
[11C]4 was 2.26 ( 0.05 (n=4).
The affinities of 4 for the μ-, δ- and κ-ORs were determined
in radioligand binding experiments in vitro using human
cloned receptors stably expressed on CHO cells (δ and
μ-OR) and HEK-293 (κ-OR) according to published
procedures.21-23 Compound 4 was found to possess high
affinity binding to κ-OR (Ki=0.12 ( 0.08 nM) and to μ-OR
(Ki=0.18 ( 0.06 nM), and lower affinity to δ-OR (Ki=5.1 (
0.6 nM).
κ-OR agonist stimulation of [35S]GTPγS binding was
measured for 4 using cloned receptors stably expressed on
CHO cellsfor μ-OR and HEK-293 cellsfor κ-OR according to
published procedures.24,25 The agonist efficacy of 4 was 105%
relative to the maximal effect of the full μ-agonist DAMGO25
and 113% relative to that of the full κ-agonist U6959322 at
Initial uptake of [11C]4 in the brain was high, with the
percent injected dose per gram of brain tissue (%ID/g) in
various brain regions ranging from 0.82 ( 0.14% in the
frontal cortex to 0.67 ( 0.08% in the cerebellum at 5 min
postinjection (pi). Over time, radioactivity was highly con-
centrated in the frontal cortex, thalamus, and striatum, where
the μ-OR expression is highest. To obtain a measure of the
specific binding to μ-OR, the radioactivity in these regions
relative to that in cerebellum was determined. The ratios
(region/cerebellum) were in the range 0.94 ( 0.14-1.22 (
0.16 at 5 min pi, 2.95 ( 0.18-3.78 ( 0.22 at 20 min pi, and
4.47 ( 0.23-5.23 ( 0.27 at 60 min pi.
Chart 1. Selected 11C-Labeled Orvinols
In separate experiments, the binding specificity and selec-
tivity of the radioligand were evaluated by pretreating the
Table 1. Regional Brain Uptake Kinetics (% Dose/g) of [11C]4 in Rats
(Mean ( SD, N = 4-5)
time after injection
region
striatum
thalamus
5 min
20 min
60 min
0.63 ( 0.11
0.73 ( 0.12
0.82 ( 0.14
0.67 ( 0.08
0.83 ( 0.27
0.87 ( 0.18
0.68 ( 0.12
0.23 ( 0.14
0.89 ( 0.25
0.78 ( 0.16
0.76 ( 0.21
0.17 ( 0.11
frontal cortex
cerebellum
Scheme 1. Synthesis of [6-O-Methyl-11C]PEO ([11C]PEO, [11C]4a
a Reagents and conditions: (i) methyl vinyl ketone, reflux, 2 h; (ii) 2-phenylethylmagnesium bromide, toluene-THF, 2 h; (iii) KOH, diethyleneglycol,
201 ꢀC; (iv) LiAlH4, THF, chlorinated methane; (v) triphenylmethyl chloride, CH2Cl2, Et3N; (vi) [11C]methyl iodide, NaH, DMF, 2:1 M HCl, EtOH;
(vii) 1 M HCl, EtOH, reflux, 4 h.

5588 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18
Marton et al.
Figure 1. Regional specific binding of
(radioactivity in region/radioactivity in cerebellum).
[
11C]4 in rat brain
Figure 2. Regional time-activity curves of [11C]4 in rat brain
(mean ( SD, N= 8). Points are activities measured in the cerebel-
lum, basal ganglia, and frontal cortex. Activity data were normali-
zed for injected dose and body weight.
animals with different pharmacological agents. When the rats
were treated with μ-antagonist cyprodime26 (2 mg/kg, iv)
10min before the injection of radioligand [11C]4 and sacrificed
20 min after, specific binding of the radioligand in the
striatum, thalamus, and frontal cortex was reduced by 86,
84, and 82% when compared with the control group
(Figure 1).
On the other hand, when the rats were treated with salvino-
rine A, a κ-OR selective agonist27,28 at a dose of 2 mg/kg,
binding of [11C]4 in the striatum, thalamus, and frontal cortex
was reduced by only 5, 7, and 11%, respectively (Figure 1).
Blocking with naloxone (1 mg/kg body weight) reduced the
binding of [11C]4 in striatum, thalamus, and frontal cortex
by >95% (Figure 1). Taken together, the results from these ex
vivo studies in rats indicate that [11C]4 has an excellent brain
uptake and a saturableandselectivebinding tothe μ-OR inrat
brain. The reason for the selective binding of [11C]4 in vivo in
ratsmayberelated tothe higher concentration of μ-OR (41%)
relative to that of κ-OR (9%) in rat brain.29
selective and specific binding to the μ-OR in striatum, thala-
mus, and frontal cortex. Micro-PET imaging experiments
confirm the specific binding of [11C]4 in vivo in rats. Blocking
of μ-OR prior to injection of the tracer reduced the specific
uptake effectively while blocking of κ-OR reduced the uptake
onlyslightly. A studyonthe useof[11C]4 for detectingchanges
to the availability of opioid receptors will be published
separately.30
Acknowledgment. We thank Prof. Dr. Meinhart H. Zenk
(Institut fur Pharmazeutische Biologie, Ludwig-Maximilians-
Universitat Munchen/Martin-Luther-Universitat Halle-
Wittenberg) for the generous gift of thebaine, and. Mrs.
Elisabeth Aiwanger and Mrs. Sybille Reder for their technical
assistance in the PET study.
Supporting Information Available: General methods, experi-
mental procedures, 1H- and 13C NMR shift values of the
prepared compounds, radiolabeling, analytical HPLC, log P
measurement, radioligand binding assays, animal experiments
(PET/CT, determination of regional brain distribution, specia-
tion of radioactivity in brain tissue). This material is available
free of charge via the Internet at http://pubs.acs.org.
Experiments were conducted to investigate whether or not
radioactive metabolites were contributing to the activity in
brain of rats receiving [11C]4. To characterize and quantify
radioactive species, rats (n=4) were injected with the tracer
and their brains were removed 40 min after injection and
homogenized. Radiolabeled species were extracted from the
homogenate with 88 ( 3% efficiency and analyzed using
reverse-phase HPLC. Radioactivity in the extracted super-
natants was determined to be g92% intact tracer at 40 min pi,
based on the limits of detection, thus representing a conserva-
tive estimate of potential metabolization. These experiments
indicate high metabolic stability of [11C]4 in brain and negli-
gible blood-brain barrier permeability and binding in the
brain of peripherally generated metabolites.
References
(1) Dhawan, B. N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley,
P. B.; Portoghese, P. S.; Hamon, M. International Union of
Pharmacology. XII. Classification of opioid receptors. Pharmacol.
Rev. 1996, 48, 567–592.
(2) Willoch, F.; Schindler, F.; Wester, H .J.; Empl, M.; Straube, A.;
Schwaiger, M.; Conrad, B.; Tolle, T. R. Central poststroke pain
and reduced opioid receptor binding within pain processing circui-
tries: a [11C]diprenorphine PET study. Pain 2004, 108, 213–220.
(3) Sprenger, T; Valet, M.; Boecker, H.; Henriksen, G.; Spilker, M. E.;
Willoch, F.; Wagner, K. J.; Wester, H. J.; Tolle, T. R. Opioidergic
activation in the medial pain system after heat pain. Pain 2006, 122,
63–67.
To further evaluate the brain uptake kinetics of [11C]4, we
conducted small-animal PET imaging experiments in rats.
These experiments confirmed the rapid entry of radioactivity
into the brain and subsequent concentration in brain regions
containing a high concentration μ-OR, such as the basal
ganglia and frontal cortex (Figure 2).
(4) Prisinzano, T. E. Natural products as tools for neuroscience:
discovery and development of novel agents to treat drug abuse.
J. Nat. Prod. 2009, 72, 581–587.
In summary, an orvinol μ- and κ-agonist radioligand,
[11C]PEO, has been successfully prepared. Evaluation of this
radioligand for its potential to label μ-OR in rats was carried
out in ex vivo biodistribution studies and in vivo micro-PET
imaging experiments in rats. [11C]PEO displays a highly
(5) Henriksen, G.; Willoch, F.; Talbot, P. S.; Wester, H. J. Recent
development and potential use of μ- and K-opioid receptor ligands
in positron emission tomography. Drug Dev. Rev. 2006, 67, 890–
904.
(6) Henriksen, G.; Willoch, F. Imaging of opioid receptors in the
central nervous system. Brain 2008, 131, 1171–1196.

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 5589
(7) Hammers, A.; Asselin, M. C.; Turkheimer, F. E.; Hinz, R.; Osman,
S.; Hotton, G.; Brooks, D. J.; Duncan, J. S.; Koepp, M. J.
Balancing bias, reliability, noise properties and the need for para-
metric maps in quantitative ligand PET: [11C]diprenorphine
test-retest data. Neuroimage 2007, 38, 82–94.
(8) Schreckenberger, M.; Klega, A.; Grunder, G.; Buchholz, H. G.;
Scheurich, A.; Schirrmacher, R.; Schirrmacher, E.; Muller, C.;
Henriksen, G.; Bartenstein, P. Opioid receptor PET reveals the
psychobiologic correlates of reward processing. J. Nucl. Med. 2008,
49, 1257–1261.
(9) Hammers, A.; Asselin, M. C.; Hinz, R.; Kitchen, I.; Brooks, D. J.;
Duncan, J. S.; Koepp, M. J. Upregulation of opioid receptor
binding following spontaneous epileptic seizures. Brain 2007, 130,
1009–1016.
(10) Boecker, H.; Sprenger, T.; Spilker, M. E.; Henriksen, G.;
Koppenhoefer, M.; Wagner, K. J.; Valet, M.; Berthele, A.; Tolle,
T. R. The runner’s high: opioidergic mechanisms in the human
brain. Cereb. Cortex 2008, 18, 2523–2531.
(11) Melichar, J. K.; Hume, S. P.; Williams, T. M.; Daglish, M. R.;
Taylor, L. G.; Ahmad, R.; Malizia, A. L.; Brooks, D. J.; Myles,
J. S.; Lingford-Hughes, A.; Nutt, D. Using [11C]diprenorphine to
image opioid receptor occupancy by methadone in opioid addic-
tion: clinical and preclinical studies. J. Pharm. Exp. Ther. 2005, 312,
309–315.
(12) Hume, S. P.; Lingford-Hughes, A. R.; Nataf, V.; Hirani, E.;
Ahmad, R.; Davies, A. N.; Nutt, D. J. Low sensitivity of the
positron emission tomography ligand [11C]diprenorphine to ago-
nist opiates. J. Pharmacol. Exp. Ther. 2007, 322, 661–667.
(13) Luthra, S. K.; Brady, F.; Turton, D. R.; Brown, D. J.; Dowsett, K.;
Waters, S. L.; Jones, A. K. P.; Matthews, R. W.; Crowder, J. C.
Automated radiosyntheses of 6-O-methyl-11C]diprenorphine and
6-O-methyl-11C]buprenorphine from 3-O-trityl protected precur-
sors. Appl. Radiat. Isot. 1994, 45, 857–873.
(14) Bentley, K. W.; Hardy, D. G. Novel Analgesics and Molecular
Rearrangements in the Morphine-Thebaine Group. III. Alcohols
of the 6,14-endo-Ethenotetrahydrooripavine Series and Derived
Analogs of N-Allylnormorphine and -norcodeine. J. Am. Chem.
Soc. 1967, 89, 3281–3292.
(15) Linders, J. T. M.; Maat, L. Face selectivity of the Diels-Alder
reaction of thebaine-like morphinandienes, a computational ap-
proach. Bull. Soc. Chim. Belg. 1989, 98, 265–276.
pharmacology of 3-hydroxy-R,R-17-trimethyl-6β,14β-ethenomor-
phinan-7β-methanol, a novel deoxygenated diprenorphine analo-
gue. Recl. Trav. Chim. Pays-Bas. 1988, 107, 449–454.
(19) Bentley, K. W.; Hardy, D. G.; Meek, B. Novel Analgesics and
Molecular Rearrangements in the Morphine-Thebaine Group. II.
Alcohols Derived from 6,14-endo-Etheno- and 6,14-endo-Ethano-
tetrahydrothebaine. J. Am. Chem. Soc. 1967, 89, 3273–3280.
(20) Bentley, K. W.; Hardy, D. G.; Crocker, H. P.; Haddlesey, D. I.;
Mayor, P. A. Novel Analgesics and Molecular Rearrangements in
the Morphine-Thebaine Group. VI. Base-Catalyzed Rearrange-
ments in the 6,14-endo-Ethenotetrahydrothebaine Series. J. Am.
Chem. Soc. 1967, 89, 3312–3321.
(21) Simonin, F.; Befort, K.; Gaveriaux-Ruff, C.; Matthes, H.; Nappey,
V.; Lannes, B.; Micheletti, G.; Kieffer, B. The human δ-opioid
receptor: genomic organization, cDNA cloning, functional expres-
sion, and distribution in human brain. Mol. Pharmacol. 1994, 46,
1015–1021.
(22) Simonin, F.; Gaveriaux-Ruff, C.; Befort, K.; Matthes, H.; Lannes,
B.; Micheletti, G.; Mattei, M.-G.; Charron, G.; Bloch, B.; Kieffer,
B. Kappa-opioid receptor in humans: cDNA and genomic cloning,
chromosomal assignment, functional expression, pharmacology
and expression pattern in the central nervous system. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 7006–7010.
(23) Wang, J. B; Johnson, P. S.; Persico, A. M.; Hawkins, A. L.; Griffin,
C. A.; Uhl, G. R. Human mu opiate receptor: cDNA and genomic
clones, pharmacologic characterization and chromosomal assign-
ment. FEBS Lett. 1994, 338, 217–222.
(24) Zhu, J.; Luo, L. Y.; Li, J. G.; Chen, C.; Liu-Chen, L. Y. Activation
of the cloned human kappa opioid receptor by agonists enhances
[
35S]GTPγS binding to membranes: determination of potencies
and efficacies of ligands. J.Pharmacol. Exp. Ther. 1997, 282, 676–
684.
(25) Alt, A.; Mansour, A.; Akil, H.; Medzihradsky, F.; Traynor, J. R.;
Woods, J. H. Stimulation of guanosine-50-O-(3-[35S]thio)tri-
phosphate binding by endogenous opioids acting at a cloned mu
receptor. J Pharmacol. Exp. Ther. 1998, 286, 282–288.
(26) Schmidhammer, H.; Burkard, W. P.; Eggstein-Aeppli, L.; Smith,
C. F. Synthesis and biological evaluation of 14-alkoxymorphinans.
2. (-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one,
a selective mu opioid receptor antagonist. J. Med. Chem. 1989,
32, 418–421.
(16) Bentley, K. W.; Hardy, D. G. Novel Analgesics and Molecular
Rearrangements in the Morphine-Thebaine Group. I. Ketones
Derived from 6,14-endo-Ethenotetrahydrothebaine. J. Am. Chem.
Soc. 1967, 89, 3267–3273.
(17) Ghosh, A. C.; Portlock, D. E.; Dalzell, H. C.; Malmberg, C.;
Herlihy, P.; Razdan, R. K.; Duax, W. L.; Smith, D. Diels-Alder
Reaction of β-Dihydrothebaine and Its 4-Phenyl Ether with
Methyl Vinyl Ketone: Synthesis of 6,14-exo-Ethenomorphinans.
J. Org. Chem. 1983, 48, 4137–4139.
(27) Hooker, J. M.; Patel, V.; Kothari, S.; Schiffer, W. K. Metabolic
Changes in the Rodent Brain after Acute Administration of
Salvinorin A. Mol. Imaging Biol. 2009, 11, 137–143.
(28) Munro, T. A.; Rizzacasa, M. A.; Roth, B. L.; Toth, B. A.; Yan, F.
Studies toward the pharmacophore of salvinorin A, a potent kappa
opioid receptor agonist. J. Med. Chem. 2005, 48, 345–348.
(29) Mansour, A.; Khachaturian, H.; Lewis, M. E.; Akil, H.; Watson,
S. J. Anatomy of CNS opioid receptors. Trends. Neurosci. 1988, 11,
308–314.
(18) Linders, J. T. M.; Kokje, J. P.; Overhand, M.; Lie, T. S.; Maat, L.
Diels-Alder reaction of 6-demethoxy-β-dihydrothebaine with
methyl vinyl ketone using microwave heating; preparation and
(30) Hjornevik, T.; Schoultz, B. W.; Marton, J. Gjerstad, J.; Drzezga, A.
Henriksen, G.; Willoch F. C-fibre LTP is associated with reduced
opioid neurotransmission in rat brain. Submitted for publication.