Free Fatty Acid Receptors

258 Pages·2017·4.87 MB·English

by  Graeme Milligan

Handbook of Experimental Pharmacology 236
Graeme Milligan
Ikuo Kimura Editors
Free Fatty
Acid
Receptors
Handbook of Experimental Pharmacology
Volume 236
Editor-in-Chief
J.E.Barrett,Philadelphia
EditorialBoard
V.Flockerzi,Homburg
M.A.Frohman,StonyBrook,NY
P.Geppetti,Florence
F.B.Hofmann,Mu¨nchen
M.C.Michel,Mainz
C.P.Page,London
W.Rosenthal,Berlin
K.Wang,Beijing
More information about this series at http://www.springer.com/series/164
Graeme Milligan (cid:129) Ikuo Kimura
Editors
Free Fatty Acid Receptors
Editors
GraemeMilligan IkuoKimura
Inst.Molecular,Cell&SystemsBiology DepofAppliedBiologicalScience
UniversityofGlasgow TokyoUnivofAgricultureandTechnology
Glasgow,Lanarkshire Fuchu-shi,Tokyo
UnitedKingdom Japan
ISSN0171-2004 ISSN1865-0325 (electronic)
HandbookofExperimentalPharmacology
ISBN978-3-319-50692-0 ISBN978-3-319-50693-7 (eBook)
DOI10.1007/978-3-319-50693-7
LibraryofCongressControlNumber:2016963340
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Preface
Recenttimeshaveseenfood-derivedproductsandmetabolites,includingfreefatty
acids, highlighted as activators of a substantial range of cell surface G protein-
coupled receptors. Four members of this broad receptor family, FFA1-FFA4, are
nowfullyacceptedasreceptorsforwhichthenaturalligandsareeithershortchain
(FFA2/FFA3) or both saturated and unsaturated longer chain (FFA1/FFA4) fatty
acids. A further G protein-coupled receptor, GPR84, is also widely recognized as
being activated by a group of medium chain fatty acids. Moreover, given that
effects of different fatty acids are viewed as being either broadly beneficial or
detrimental to health, recognition of the effects of various fatty acids via these G
protein-coupled receptors has resulted in considerable interest in the potential to
target their effects therapeutically by either activating or blocking one of more
members of the free fatty acid receptor group with synthetic small molecule
ligands.Todate,themajorfociofinterestinclinicalsettingshavecentredoneither
activating the long chain fatty acid receptors to enhance insulin release from
pancreatic islets, to improve insulin sensitivity and to provide potential anti-
inflammatory input in metabolic diseases, or antagonizing short- and medium-
chain fatty acid receptors to limit neutrophil and other white cell chemotaxis and
toassessifthismightprovideameanstolimitthedevelopmentormaintenanceof
inflammatoryconditionsofthelowerbowel.Althoughnomedicinesthattargetone
ofmoreofthefreefattyacidreceptorshaveyetbeenapprovedforpatienttreatment,
theprogressoftheFFA1agonistfasiglifamintoaphaseIIIclinicaltrialbeforethis
trial was halted due to deleterious effects on liver transporter systems, provided
strong validation of activation of this receptor as a means to provide glycaemic
control. Whilst no FFA4 ligands have entered clinical trials to date, activation of
thisreceptorisalsoviewedasaconceptuallyattractivemeanstoimprovemetabolic
function. Neither the FFA2 antagonist GLPG0974 nor the GPR84 antagonist
GLPG1205 proved effective for the treatment of ulcerative colitis, but recent
publications on both of these receptors suggest a broader range of other potential
therapeuticareasthatmightbetargeted,whilstpublicationsonaspectsoffreefatty
acidregulationofcancerdevelopmentandprogression,bothpositiveandnegative,
v
vi Preface
anditseffectsonadipocyteversusbonedifferentiationalsohighlightdifferentroles
ofthelongchainfattyacidreceptors.
ThegroupofreviewsbyleadingexpertsthatcomprisethisvolumeofHandbook
of Experimental Pharmacology therefore covers topics that range from basic
underpinning knowledge of the biology and physiology regulated by members of
the free fatty acid receptor family, through the chemistry and generation of syn-
theticligands,bothtoolcompoundsandthedevelopmentofdruglike-molecules,to
theclinicalpotentialofsuchligands,andwellasanalysisoftheopportunitiesand
challenges that remain. With a single atomic level structure of a free fatty acid
receptoravailabletodate,thentheincorporationofeffortstoprovidebothhomol-
ogy models and mutagenic analysis of the modes of binding of free fatty acid
receptorligandsandwhethersuchligandsbindinamannerthatiscompetitivewith
thatoftheendogenousfattyacidsisalsoexplored.Frominitialde-orphanizationin
theearliestyearsofthecenturyandrathermodestnumbersofreportedstudiesinthe
earlydays,therehasbeenarapidaccelerationofinterestinandknowledgeofthe
freefattyacidreceptorsthatreflectsthestillgrowingappreciationoftheirrolesand
theirpotentialfortherapeuticregulation.Itisthereforeanidealtimetoconsiderand
reviewtheprogresstodateandprospectsforthefuture.
Glasgow,UK G.Milligan
Tokyo,Japan I.Kimura
October2016
Contents
LigandsatFreeFattyAcidReceptor1(GPR40). . . . . . . . . . . . . . . . . . 1
TakafumiHara
LigandsattheFreeFattyAcidReceptors2/3(GPR43/GPR41). . . . . . . 17
GraemeMilligan,DanieleBolognini,andEugeniaSergeev
PharmacologicalToolCompoundsfortheFreeFattyAcid
Receptor4(FFA4/GPR120). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
SteffenV.F.HansenandTrondUlven
ApplicationofGPCRStructuresforModellingofFreeFatty
AcidReceptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
IrinaG.Tikhonova
UsingBiosensorstoStudyFreeFattyAcidReceptorPharmacology
andFunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
BrianD.Hudson
KeyQuestionsforTranslationofFFAReceptors:
FromPharmacologytoMedicines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
ArthurT.SuckowandCeliaP.Briscoe
PolymorphicVariationinFFAReceptors:Functions
andConsequences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
AtsuhikoIchimura
TheRoleandFutureofFFA1asaTherapeuticTarget. . . . . . . . . . . . . 159
JulienGhislainandVincentPoitout
GutHormoneRegulationandSecretionviaFFA1andFFA4. . . . . . . . 181
FionaM.Gribble,EleftheriaDiakogiannaki,andFrankReimann
FFA2andFFA3inMetabolicRegulation. . . . . . . . . . . . . . . . . . . . . . . . 205
CongTangandStefanOffermanns
vii
viii Contents
Anti-InflammatoryandInsulin-SensitizingEffectsofFreeFatty
AcidReceptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
JunkiMiyamoto,MayuKasubuchi,AkiraNakajima,andIkuoKimura
FreeFattyAcidReceptorsandCancer:FromNutrition
toPharmacology.. . . .. . . .. . . .. . . . .. . . .. . . .. . . .. . . .. . . .. . . .. 233
MandiM.HopkinsandKathrynE.Meier
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Ligands at Free Fatty Acid Receptor 1
(GPR40)
Takafumi Hara
Contents
1 Introduction................................................................................... 2
2 NaturalLigands............................................................................... 3
3 SyntheticLigands............................................................................. 3
3.1 Agonists................................................................................. 3
3.2 Antagonists............................................................................. 7
3.3 FluorescentLigands.................................................................... 7
4 Structure–ActivityRelationships............................................................. 8
5 CrystalStructureofFFA1withTAK-875................................................... 8
6 BiasedAgonismofFFA1Ligand............................................................ 9
7 ClinicalTrials................................................................................. 10
8 Conclusions................................................................................... 12
References........................................................................................ 12
Abstract
FFA1isaGprotein-coupledreceptoractivatedbymedium-tolong-chainfatty
acids. FFA1 plays important roles in various physiological processes such as
insulinsecretionandenergymetabolism.FFA1expressedonpancreaticβ-cells
and intestine contributes to insulin and incretin secretion, respectively. These
physiological functions of FFA1 are interesting as an attractive drug target for
type II diabetes and metabolic disorders. A number of synthetic FFA1 ligands
havebeendevelopedandtheyhavecontributedtoourcurrentunderstandingof
thephysiologicalandpathophysiologicalfunctionsofFFA1bothininvitroand
T.Hara(*)
DepartmentofPathology,StanfordUniversitySchoolofMedicine,300PasteurDrive,Lane235,
Stanford,CA94305-5324,USA
FacultyofPharmaceuticalSciences,Tokushima-BunriUniversity,Nishihama,Yamashiro-cho,
Tokushima770-8514,Japan
e-mail:[email protected]
#SpringerInternationalPublishingAG2016 1
G.Milligan,I.Kimura(eds.),FreeFattyAcidReceptors,
HandbookofExperimentalPharmacology236,DOI10.1007/164_2016_59