Table Of ContentResearch and Development of
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In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
1131
ACS SYMPOSIUM SERIES
Research and Development of
Opioid-Related Ligands
Mei-Chuan Ko, Editor
org 01 Wake Forest University
cs.w0 Winston-Salem, NorthCarolina, UnitedStates
http://pubs.a2013-1131.f StephenUnMive.rHsituysobfaBnadths, Editor
013 | 1/bk- Bath, United Kingdom
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AmericanChemicalSociety,Washington,DC
DistributedinprintbyOxfordUniversityPress
In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
org 01
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PRINTEDINTHEUNITEDSTATESOFAMERICA
In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
Foreword
The ACS Symposium Series was first published in 1974 to provide a
mechanism for publishing symposia quickly in book form. The purpose of
the series is to publish timely, comprehensive books developed from the ACS
sponsoredsymposiabasedoncurrentscientificresearch. Occasionally,booksare
org 01 developed from symposia sponsored by other organizations when the topic is of
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In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
Preface
Research in the opioid field continues apace, with ongoing developments in our
understanding of the underlying biology through to the clinical consequences of modulating
opioid receptors. The sheer volume of research being carried out in this field precludes a
thorough bench-to-bedside review and has necessitated a somewhat focused approach within
thisvolume, inparticulartheuseandpotentialusesofligandsthatactivateone, ormore, of
1
0
0 thereceptors. ContributionstoResearchandDevelopmentofOpioid-RelatedLigandsinclude
pr
1. chaptersdescribingcurrentresearchintothemainclinicalusesofopioids,analgesiaandopioid
3
1
1 abusetreatment,aswellaswhattheeditorsconsidertobekeyareasofpre-clinicaldevelopment.
3-
1 Not surprisingly the identification of a fourth opioid-like receptor, the NOP receptor, has
0
2
k- providedthestimulusformanystudieswiththeaimofdeterminingthepotentialtherapeutic
b
1/ value of modulating the activity of this receptor. A number of chapters within this volume
2
0
1 reflectthecurrentinterestinthisnewmemberofthefamily.
0.
s.org doi: 1 5themThees,1s6tacrhtianpgtewrsitohftRheescelainrcichaalnsdtuDdieevseloofppmaeinntaonfdOoppiiooiidd-RaebluasteedtrLeaigtmanednstaarnedafrorallnogwededinbtoy
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013 | b): M foofrsouncehrleicgeapntdosrhoarsanaolltohweredcotnhteinpuhesartmoabceoloofgysubosftathnetiaNlOinPterreescte,patnodr itnodbeeeds,tuthdeieadvainiladbeiltiatiyl
2e
3, W fromsoonafteritsdiscovery. Interestingly,ligandsinducedistinctreceptorconformationsand
ay 1ate ( producedifferentsignalingcascades,indicatingthatligand-directedsignalingorbiasedagonism
MD
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UNIPublic emffiadceaciynaatneuamchb)ecraonfbtheedcehsaigpnteerds.. Therationalefor,andprogressin,targetingsuchligandsis
Itishopedthatthevolumewillprovideausefulreferenceresourcebutalsostimulatefurther
researchanddebatewithintheopioidresearchcommunity.
Mei-ChuanKo, Ph.D.
Department of Physiology and Pharmacology, Wake Forest University School of Medicine,
Winston-Salem,NC27157,USA
[email protected](e-mail)
StephenM.Husbands,Ph.D.
DepartmentofPharmacyandPharmacology,UniversityofBath,ClavertonDown,
Bath,BA27AY,UK
[email protected](e-mail)
xi
In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
Chapter 1
Commentary on the Current Status of Clinically
Used Analgesics
Thomas M. Dodds*
org 01 DepartmentofAnesthesiology,GeiselSchoolofMedicine,
s.acs.1.ch0 DartmouthHitchcockMedicalCenter,OneMedicalCenterDrive,Lebanon,
ub13 NewHampshire03756,USA
p1
p://13- *E-mail: [email protected]; Phone: 603-650-6177;
htt20 Facsimile: 603-650-8980
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011/
22
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y 110. Pain is universally experienced and necessary for prevention of physical
Maoi: injury and, ultimately, for survival. The experience of pain has a price. The
M on 13 | d medical community has gained an increasing awareness of adverse physical,
A20 economic and social consequences of pain. Pain and its consequences are
GH10, widespread. Estimates are that up to 1.5 billion people worldwide experience
MINMay chronic pain (1). The chronic pain population in the United States alone is
BIRb): estimated at approximately 115 million and data show associated costs for
V We pain in terms of treatment and lost productivity far exceed the annual costs of
y UNIDate ( shueragretrdyisaedadsseaonracdadnitcieorna(l2,)a.ndAscuubtsetapnatiianl,absusordceiantetodtwheitsheeasctciimdeantetsa.l Ainljtuhroyugohr
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Do P pain, especially dynamic pain, is prevalent with approximately two-thirds of
postoperative patients experiencing moderate to severe or extreme pain after
surgery (4). The imperative imposed by these observations is underscored by
recentdatatoshowthateffectivetreatmentofacutepainaftersurgeryimproves
recoveryandlong-termoutcomes(5,6).
For centuries, opiate medications have been used to treat human pain due
to their potency, effectiveness and availability. Opiates remain the mainstay for
treatmentofsevereacuteand,increasingly,chronicpain. However,thesideeffect
profileofopiatesissubstantialwithatleast25%ofacutepainpatientsexperiencing
clinicallysignificantsideeffects,evenwhentheirpainisundertreated(4),andwith
asubstantialpercentageofchronicpainpatientsatriskforthesamesideeffects
andopiatedependence. Adjuvantanalgesicscanimprovethemanagementofpain,
usuallydefinedasreducedneedforopiatesandoccasionallyasimprovedqualityof
©2013AmericanChemicalSociety
In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
pain control. Unfortunately, all currently available adjuvant agents have limited
effectiveness compared to opiates and each has significant side effects that can
limitusesuchasbleeding,sedation,dysphoria,orhepato-renaltoxicity.
Against this backdrop, no truly new class of drugs for the treatment of
moderate to severe pain has been introduced into clinical medicine since the
development of indomethacin as the first non-steroidal anti-inflammatory drug
in the 1960s. With our emerging understanding regarding the frequency of
ineffectivepaincontrol, theadverseconsequencesofopiatesideeffects, andthe
benefitsofmoreeffectivepaincontrol,thereisaclearneedforthedevelopment
of new drugs to treat human pain. The clinical and research environment are in
need of a fresh and timely examination of alternative opiate medications. The
present volume, with contributions from many experts in the field of alternative
opiate drugs, is an important review of current and future drug development. It
org 01 willbewelcomedbyscientistsandcliniciansalikewhoseektoimprovethecare
s.acs.1.ch0 ofthemanypatientswhoneedmoreeffectiveanalgesia.
b3
u1
p1
p://13-
htt20 References
3 | bk-
011/
3, 2102 1. IOM(InstituteofMedicine). CommitteeonAdvancingPainResearchC,and
y 110. Education; Institute of Medicine. Relieving Pain in America: A Blueprint
Maoi: forTransformingPrevention,Care,Education,andResearch;TheNational
M on 13 | d AcademiesPress: Washington,DC,2011.
A20 2. Gaskin,D.J.;Richard,P.J.Pain2012,13,715–724.
GH10, 3. Kehlet,H.;Jensen,T.S.;Woolf,C.J.Lancet2006,367,1618–1625.
MINMay 4. Apfelbaum,J.L.;Chen,C.;Mehta,S.S.;Gan,T.J.Anesth. Analg. 2003,97
BIRb): (2), 534–540.
V We 5. Loftus, R. W.; Yeager, M. P.; Clark, J. A.; Brown, J. R.; Abdu, W. A.;
y UNIDate ( 6. BSeunvgaunpetnad,rDan.,KA.;.B; eKarcohi,nM, J..LS..A;nDesetlhiaesVioallolge,yC20.1J0.;,1K13ar(i,3)M,6.;39M–6o4ri6c., M.;
nloaded bblication Tuman,K.J.Anesth. Analg. 2010,110(1),199–207.
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In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
Chapter 2
Commentary on the Current State of
Opioid-Related Research
John W. Lewis*
g
or
cs.02 DepartmentofPharmacyandPharmacology,UniversityofBath,
a0
ubs.1.ch ClavertonDown,BathBA27AY,UK
http://p13-113 *E-mail: prxjwl@Fbaxa:th4.a4c(0.u)1k2;2P5h-3o8n6e1:1444(0)1225-383103;
13, 2013 | 021/bk-20 Morphinehasbeenthe“goldstandard”ofclinicalanalgesicssinceitsisolation
ay 0.1 fromopiuminthemiddleoftheC19th. Thoughitsunequivocalstructurewasnot
M1
ANA on 013 | doi: dsbieudtteenremofftiengcertdes,audtlneytpisleun1cd9ce2en5sc,seftu/htleo.lseDeraaurnrccihnegfaontrhdeimrelapssprtoirvnaeetomarreylyndt5es0plrayecseksaiinrosgnw,mhhoaersnpbhIeienhnea’vcseopnbrtieinnecuniopiunles,
B2
R0, orclosetothefield,majoradvancesintermsoftheidentificationofthreetypesof
U1
OIS May opioid receptor – mu (MOP), kappa (KOP) and delta (DOP) – and their cloning
LLINWeb): hliakvee”rbeeceenptmoraadned. iMtsonraeturreaclelnigtlaynd(1N9/9O4F)Qthehaisdgenivtiefincfarteioshniomfpaetfuosutrothdi“socpoivoeirdy-
UNIV IDate ( rceusreraerncthvporluomgreaminmwehs.icThhperseeceevdeenntcseairsegrievfleenctteodliignatnhdesbhaalvanincgeNofOcPhaapctteivrsitiynatnhde
by on itspotentialtoproducenon-rewardinganalgesicsandsubstanceabusetreatments.
nloaded Publicati andDThOePmagajoonrisetfsfoarsts“nboyn-tahdedpichtainrmg”acaenuatligceaslicinsdhuasvtreyntooteyxieplldoeidt smeluecchtivsuecKceOssP,
w though butorphanol and nalbuphine, mixed MOP/KOP partial agonists have
o
D
found limited clinical use. Interest in KOP agonists lacking CNS penetration
as peripheral analgesics for the treatment of visceral pain continues as it does
for DOP ligands in bifunctional opioids with MOP agonists. These aspects are
coveredinchaptersinthecurrentvolume.
AnextremelyusefultimelineforthehistoryofN/OFQandselectivepeptide
andnon-peptideNOPagonistsandantagonistsisshowninCalo’schapter,which
isprimarilyconcernedwithpeptideligandsforNOP.Thoughthereisnochapter
devotedtonon-peptideNOPagonistsandantagoniststherearerecentreviewsof
thistopicandtheirstructure–activityrelationshipsandpharmacologyarecovered
in this volume in the chapters of Zaveri, Toll, Whiteside and Ko. In the latter,
the important differences between non-human primates and rodents in terms of
supraspinalandsystemiceffectsofNOPagonistsarediscussed. Theagonistsin
©2013AmericanChemicalSociety
In Research and Development of Opioid-Related Ligands; Ko, M., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
