Dopamine Receptors - Tocris Bioscience

More documents

Recommendations

Info

Tocris Bioscience Scientific Review SeriesBox 1: Dopamine receptor productsBox 1 | Dopamine synthesis and metabolismHOHODopamine (3548)Endogenous dopaminereceptor agonistNH 2NO 2 OO NHOHNPEC-caged-dopamine (3992)Caged version of dopamineSO 2 MeOHin the human population with variants containing differentlength insertions in I3. 16,17 In some cases, these D 2-like receptorvariants may have differential abilities to couple to or activateG proteins, 18,19 and may also exhibit slightly different pharmacologicalproperties. 16,20,21 Lines of mice have been developed inwhich the I3 insertion that produces the long D 2receptor variant(D 2L) is deleted, resulting in the expression of only the shortvariant (D 2S). Characterization of these mice suggests that thesplice variants are not fully interchangeable; some D 2receptorresponses are not observed in mice that express only D 2S. 22-24The variants of the D 4receptor have not been found to exhibitany substantive differences in agonist signaling or in couplingto G proteins. 25HOHONH 2L-DOPA (3788)Dopamine precursorCO 2 HHNOSU 6162 (2599)Dopamine stabilizerThe individual properties of the different subtypes were initiallyprobed by expressing the receptors in recombinant cellsand examining the localization of the subtypes at the mRNAand protein level. More recently, the use of subtype-selectivedrugs and transgenic mice with one or more receptor subtypesgenetically deleted has enabled further study of these receptors.Properties of the Dopamine Receptor SubtypesCommon receptor propertiesAnalysis of the amino acid sequences of the dopamine receptorsubtypes has shown that significant homologies exist amongthe subtypes, with the greatest being found between membersof either subfamily. 7,8 Each receptor has been shown to containseven stretches of amino acids that are hydrophobic and longenough to span the membrane. It seems therefore that eachof the dopamine receptors conforms to the general structuralmodel for a GPCR, 9-11 with an extracellular amino terminusand seven putative membrane spanning α-helices linked byintracellular and extracellular protein loops (Figure 2). One ormore potential sites for glycosylation are found on the aminoterminus and second extracellular loop. The helices are bundledtogether in the membrane to form the ligand binding site(Figure 2); some information is available on the residues thatmake contact with ligands. 11,12 There is an intracellular carboxylterminus, probably bearing a palmitoyl group, which may forma further link to the membrane. The D 1‐like receptors haveshort third intracellular loops and long carboxyl terminal tails,whereas the D 2‐like receptors have long third intracellular loopsand short carboxyl terminal tails. This provides a structuralbasis for the division of the receptors into two subfamilies butis also likely to have a functional significance, possibly relatedto the specificity of receptor/G protein interaction.The third intracellular loop, termed ‘I3’, is important for theinteraction of the receptor and G protein. For the D 2‐likereceptors, variants of the subtypes exist based on this loop. Forexample, there are short and long splice variants of the D 2andD 3receptors with the long forms having an insertion (29 aminoacids for the long D 2, D 2L) in this loop. 13,14 Polymorphic variantsof the D 2receptor have been described with single aminoacid changes in I3. 15 The D 4receptor is highly polymorphicIndividual receptor propertiesThe dopamine receptor subtypes exhibit different propertiesin terms of their pharmacological profile, localization,and mechanism of action; these differences will be brieflysummarized below.D 1-like receptorsBoth the D 1and D 5receptors show pharmacological propertiessimilar to those of the original pharmacologically defined D 1receptor, that is, a high affinity for the benzazepine ligands SCH23390, SCH 39166, and SKF 83566, which are selective antagonistsfor these subtypes. Although not as selective for D 1overD 2as the benzazepine antagonists, LE 300 is a potent D 1‐likeantagonist that is useful because it is structurally distinctfrom the benzazepines. Thioxanthines such as flupentixol andFigure 1 | Regulation of adenylyl cyclase by D 1and D 2dopaminereceptorsDopamineβγGα sD 1-like receptorAC+ –ATPcAMPD 2-like receptorDopamineGα i/oThe diagram shows the effects of dopamine to stimulate or inhibitadenylyl cyclase (AC) via the D 1-like receptor and G protein Ga sorthe D 2-like receptor and G protein Ga i/o, respectively.βγ2 |
Dopamine ReceptorsTable 1 | Dopamine receptor subtypes defined from physiological, pharmacological, and biochemical studiesPhysiological FunctionsBiochemical ResponsesD 1-like ReceptorsAspects of motor and cognitive function (brain),cardiovascular functionAdenylyl cyclase↑Phospholipase C↑LocalizationCaudate nucleus, putamen, nucleus accumbens,olfactory tubercle, cerebral cortex, cardiovascularsystemReceptor Antagonists SCH 23390SCH 39166SKF 83566LE 300Receptor Agonists A 77636SKF 38393SKF 81297A 68930SKF 81297DoxanthrineRadioligands [ 3 H]-SCH 23390*[ 125 I]-SCH 23982D 2-like ReceptorsAspects of motor function and behavior (brain), control of prolactin andα-MSH secretion from pituitary, cardiovascular functionAdenylyl cyclase↓K + channel activity↑Ca 2+ channel activity↓GSK-3b↑Caudate nucleus, putamen, nucleus accumbens, olfactory tubercle,cerebral cortex, anterior and neurointermediate lobes of pituitary gland,cardiovascular systemDomperidoneNemonaprideRaclopride(S)-(-)-SulpiridePHNOQuinpiroleN-0437RotigotineSumanirole[ 3 H]-Nemonapride (YM-09151-2)[ 3 H]-Raclopride[ 3 H]-Spiperone**(Bold text denotes compounds available from Tocris at time of publication)The localization data are from functional and ligand-binding studies on dispersed tissues and tissue slices. *[ 3 H]-SCH 23390 can also bind to 5-HT 2receptors if present;**[ 3 H]-Spiperone can also bind to 5-HT 1A, 5-HT 2receptors, and α 1‐adrenoceptors if present.phenothiazines such as fluphenazine also show high affinity butare not selective for D 1-like over D 2-like receptors. The developmentof the first D 1-like receptor agonist, SKF 38393, wasimportant for differentiating between activation of D 1‐like andD 2‐like receptors, although it was later realized that the partialagonist nature of SKF 38393 produced an under-appreciation ofthe contribution of D 1-like receptors to behavior. 26 The D 1‐likereceptors show moderate affinities for typical dopamine agonistssuch as apomorphine; full and/or selective D 1-like receptoragonists such as such as A 77636, A 68930, SKF 81297, dihydrexidine,and doxanthrine are now available (Box 2). Thereare minor differences in the affinities of some compounds forthe D 1and D 5receptors (higher agonist and lower antagonistaffinities for D 5), but no compounds that effectively distinguishbetween those subtypes are as yet available. 27,28D 1receptors are found at high levels in the typical dopaminerichregions of brain such as the neostriatum, substantia nigra,nucleus accumbens, and olfactory tubercle, whereas the distributionof the D 5receptors is much more restricted (Table 2);this subtype is found generally at much lower levels. Bothreceptors are able to stimulate adenylyl cyclase (Figure 1), withthe D 5receptor showing some constitutive activity for thisresponse. 28 Inverse agonist activity at the D 1and D 5receptorsis seen in recombinant systems for some compounds such asbutaclamol, 28 which were previously considered to be antagonists.It has been known for some time that stimulation of aD 1-like receptor leads to activation of phospholipase C 29 andrecently this response has been linked to the D 1/D 2receptorheterodimer, providing a function for heterodimer formation. 30Agonists that preferentially stimulate the cAMP response(SKF 83822) or the phospholipase C response (SKF 83959)associated with D 1-like receptors have been described. 31The D 1receptor seems to mediate important actions ofdopamine to control movement, cognitive function, andcardio vascular function. Direct interactions between D 1‐likereceptors and ion channel-linked receptors have been described(D 1/NMDA, D 5/GABA A), 32 leading to modulation of receptorfunction. These interactions provide for cross talk between fastand slow neurotransmitter systems and may point towards afurther functional role for the D 5receptor, which is not wellunderstood. Studies with null mutant ‘knock-out’ mice havesuggested that in some respects, the functions of the D 1andD 5receptors are reciprocal – for example, with respect tospontaneous locomotion – and in other respects similar, forexample with respect to grooming or psychostimulant-inducedlocomotion. 33,34D 2-like receptorsOverall, the D 2, D 3and D 4receptors exhibit pharmacologicalproperties similar to those of the originally defined D 2receptor;that is, they all show high affinities for drugs such as thebutyrophenones (haloperidol, spiperone) and substitutedbenzamides (sulpiride, raclopride), and these classes of drugsprovide selective antagonists for D 2-like receptors over D 1-likereceptors (Table 3). As indicated above, the D 2‐like receptorsalso show high affinities for phenothiazines and thioxanthines.Each D 2‐like receptor has its own pharmacological signature,so there are some differences in affinities of drugs for the individualD 2‐like receptors (Box 3). For example, sulpiride andraclopride show high affinity for the D 2and D 3receptors butwww.tocris.com | 3
Page 1: Dopamine ReceptorsPhilip G. Strange
Page 5 and 6: Dopamine ReceptorsTable 2 | Dopamin
Page 10 and 11: Tocris Bioscience Scientific Review
Page 12: © 2013 Tocris Cookson, Ltd.www.toc

Dopamine Receptors - Tocris Bioscience

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?