Table 1.
Purinergic receptor subtype properties
| Receptor | Main distribution | Agonists | Antagonists | Transduction mechanisms |
|---|---|---|---|---|
| P1 | ||||
| P1A1 | Brain, spinal cord, testis, heart, autonomic nerve terminals | CCPA>R-PIA = S-ENBA, CVT-510, GR79236, 2′-MeCCPA, SDZ WAG 994, INO-8875, MRS 5474 | DPCPX, N-0840, MRS1754, WRC-0571, PSB36, SLV320, CGS 16943 | Gi/Go ↓cAMP |
| P1A2a | Brain, heart, lungs, spleen | HENECA>CGS 21680 = CVT-3146, ATL-146e, Regadenoson | KF17837, SCH58261, ZM241385, KW 6002 | GS ↑cAMP |
| P1A2b | Large intestine, bladder | Bay60-6583, NECA | PSB603, MRE-2029-F20, MRS1754, PSB0788 MRS1706, PSB1115, Alloxazine, GS-6201 | GS ↑cAMP, Gq/G11 |
| P1A3 | Lung, liver, brain, testis, heart | IB-MECA>MRS5698 > MRS5168 > 2-Cl-IB-MECA, DBXRM, VT160, HEMADO | MRS1220, L-268605, MRS1191, MRS1523(rat), VUF8504, VUF5574, MRS1334(human), PSB10 | Gi/Go, Gq/G11, ↓cAMP, PLC-β activation |
| P2 | ||||
| P2X1 | Smooth muscle, platelets, cerebellum, dorsal horn spinal neurons | BzATP > ATP = 2-MeSATP≥α,β-meATP=L-β,γ-meATP (rapid desensitization), PAPET-ATP | NF864 > NF449 > IP5I≥TNP-ATP> RO 0437626 > NF279, NF023, RO1, MRS2159 | Intrinsic cation channel (Ca2+ and Na+) |
| P2X2 | Smooth muscle, CNS, retina, chromaffin cells, autonomic and sensory ganglia, pancreas | ATP≥ATPγS≥2-MeSATP≫α,β-meATP (pH + zinc sensitive), β,γ-CF2ATP | PSB-1011 > RB2, isoPPADS>PPADS>Suramin, NF770, NF778, Aminoglycoside | Intrinsic ion channel (particularly Ca2+) |
| P2X3 | Sensory neurons, NTS, some sympathetic neurons | 2-MeSATP≥ATP≥Ap4A≥α,β-meATP (rapid desensitization), PAPET-ATP, BzATP | TNP-ATP, AF353, A317491, RO3, isoPPADS > NF110 > PPADS, Ip5I, phenol red, RN-1838, Spinorphin | Intrinsic cation channel |
| P2X4 | CNS, testis, colon, endothelial cells, microglia | ATP≫α,β-meATP≫ CTP, 2-MeSATP Ivermectin potentiation | 5-BDBD≫ TNP-ATP, PPADS>BBG, Paroxetine, phenolphthalein, CO donor (CORM 2), 5MPTP | Intrinsic ion channel (especially Ca2+) |
| P2X5 | Proliferating cells in skin, gut, bladder, thymus, spinal cord, heart, adrenal medulla | ATP=2-MeSATP=ATPγS≫α,β-meATP>AP4A | BBG>PPADS, Suramin | Intrinsic ion channel |
| P2X6 | CNS, motor neurons in spinal cord | - (only functions as a heteromultimer) | – | Intrinsic ion channel |
| P2X7 | Immune cells including dendritic cells (mast cells, macrophages), pancreas, skin, microglia | BzATP>ATP ≥2-MeSATP ≫α,β-meATP (clemastine potentiates) | KN62, BBG, KN04, MRS2427, O-ATP, RN-6189, Perazine, AZ10606120, A740003, A-438079, A-804598, GSK-1370319, Comp 31 (GSK), AZD-9056, CE-224,535, JNJ-47965567, JNJ-42253432 (penetrates BBB), decavanadate | Intrinsic cation channel and a large pore with prolonged activation |
| P2Y1 | Epithelial and endothelial cells, platelets, immune cells, osteoclasts, brain | MRS2365 > 2-MeSADP=Ap5(γB)≫ ADPβS>ATP >2-MeSATP=ADP | MRS2500 > MRS2279 > MRS2179, PIT, A3P5P | Gq/G11, PLC-β activation |
| P2Y2 | Immune cells, epithelial and endothelial cells, kidney tubules, osteoblasts | 2-thio-UTP>UTP, MRS2698 ≥ ATP, INS 365 > INS 37217, UTPγS>Ap4A>MRS 2768, Up4-phenyl ester | AR-C126313 > Suramin> RB2, PSB-716, MRS2576, PSB-0402 | Gq/G11 and possibly Gi/Go, PLC-β activation |
| P2Y4 | Endothelial cells, placenta, spleen, thymus | 2′-azido-dUTP> UTPγS, UTP≥ATP≥ Ap4A Up4U MRS4062 | ATP (human)>Reactive Blue 2 > Suramin, MRS2577, PPADS | Gq/G11 and possibly Gi, PLC-β activation |
| P2Y6 | Airway and intestinal epithelial cells, placenta, T cells, thymus, microglia (activated) | MRS2693 > UDPβS, PSB0474 > INS48823, Up3U, 3-phenacyl-UDP≫ UDP>UTP≫ ATP, α,β-meUDP, MRS2957, MRS4129, 5-OMe-UDP αB | MRS2578 > Reactive Blue 2, PPADS, MRS2567, MRS2575 (human) | Gq/G11, PLC-β activation |
| P2Y11 | Spleen, intestine, granulocytes | ATPγS>AR-C67085>BzATP≥ATP, NF546, NAD+, NAADP+, Sp-2-propylthio-ATP-α-B | NF157 > Suramin>RB2, 5′-AMPS, NF340, AMP-α-5, | Gq/G11 and GS, PLC-β activation |
| P2Y12 | Platelets, glial cells | 2-MeSADP≥ADP>ATP, ADP-β-S | AR-C69931MX> AZD6140 (Ticagrelor), INS50589 > RB2 > 2-MeSAMP AR-C66096, CT50547,PSB-0413, Carba-nucleosides, MRS2395, AR-C67085, [3H]PSB-0413, clopidogrel, AZD1283 | GαI, inhibition of adenylate cyclase |
| P2Y13 | Spleen, brain, lymph nodes, bone marrow, erythrocytes | ADP=2-MeSADP>2-MeSATP, ATP | AR-C69931MX>AR-C67085 > MRS2211, 2-MeSAMP | Gi/Go |
| P2Y14 | Placenta, adipose tissue, stomach, intestine, discrete brain regions, mast cells | MRS2690 > UDP>UDP glucose≥UDP-galactose, UDP-glucosamine, MRS2905 | PPTN | Gq/G11 |
| GPR17 | Oligodendrocytes | Uracil nucleotides/cysteinyl-leukotrienes, MDL29,951 | PZB01415033 | Gi, adenylate cyclase inhibition |
P2X receptor subtype agonist potencies are based on rat preparations, whereas P1 and P2Y receptor subtype agonist potencies are based on human preparations. Modified with permission from Burnstock (115).
≫, much greater affinity than; >, greater affinity than; ≥, greater or equal affinity than.
A317491, 5-[[[(3-phenoxyphenyl)methyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1,2,4-benzenetricarboxylic acid; A3P5P, adenosine-3′-5′-bisphosphate; A-438079, 3-[[5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride; A740003, N-[1-[[(cyanoamino)(5-quinolinylamino)methylene]amino]-2,2-dimethylpropyl]-3,4-dimethoxybenze-neacetamide; A-804598, N-cyano-N″-[(1S)-1-phenylethyl]-N′-5-quinolinyl-guanidine; ADP, adenosine 5′-diphosphte; ADPβS, adenosine-5′-(β-thio)-diphosphate; AF353, 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine; 5′-AMPS, 5′-O-thiomnophosphate; Ap4A, diadenosine tetraphosphate; Ap5(γβ), adenosine pentaphosphate (βγ); ATL-146e, 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester; Ap4A, diadenosine tetraphosphate; ATPγS, adenosine-5′-(γ-thio)-triphosphate; AR-C126313, 2′-amino-2′-deoxy-2-thiouridine 5′-triphosphate; AR-C66096, 2-(propylthio)adenosine-5′-O-(β,γ-difluoromethylene)triphosphate; AR-C67085, [[[[(2R,3S,4R,5R)-5-(6-amino-2-propylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]-dichloromethyl]phosphonic acid; AR-C69931MX, [dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] oxy-hydroxyphosphoryl]methyl]phosphonic acid; ATP, adenosine 5′-triphosphte; ATPγS, adenosine-5′-(γ-thio)-triphosphate; AZ10606120, N-[2-[[2-[(2-hydroxyethyl)amino]ethyl] amino]-5-quinolinyl]-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide dihydrochloride; AZD1283, ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate; ZD6140, 3-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylsulfanyltriazolo[5,4-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; 2′-azido-dUTP, 2′-azido-deoxyuridine-5′-triphosphate; Bay 60-6583, 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide; BBG, brilliant blue green; 5-BDBD, 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one; BzATP, 2′ (3′)-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate; β,γ-CF2ATP, α,β-difluoromethylene-ATP; cAMP, cyclic AMP; CCPA, chlorocyclopentyl adenosine; CGS 21680, 2-[p-(2-carboxyethyl)phenethylamino]-5¢-N-ethylcarboxamido adenosine; 2-Cl-IB-MECA, 2-Chloro-N6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-β-D-ribofuranosyl]adenine; CNS, central nervous system; CORM 2, carbon monoxide donor 2; CT50547, N1-(6-ethoxy-1,3-benzothiazol-2-yl-2-(7-ethoxy-4-hydroxy-2,2-dioxo-2H-2] 6benzo-[4,5][1,3]thiazolo[2,3-c][1,2,4] thiadiazin-3-yl)-2-oxo-1-ethanesulfonamide; CTP, cytosine triphosphate; CVT-3146, 2-(N-pyrazolyl) adenosine; CVT-510, N-(3(R)-tetrahydrofura-nyl)-6-aminopurine riboside; DBXRM, 1,3-Dibutylxanthine 7-riboside 5′-N-methylcarboxamide; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; GR79236, N-[(1S,trans)-2-hydroxycyclo-pentyl]adenosine; GS-6201, 3-Ethyl-3,9-dihydro-1-propyl-8-[1-[[3-(trifluoromethyl)phenyl]methyl]-1H-pyrazol-4-yl]-1H-purine-2,6-dione; GSK-1370319, N-[(2,4-dichlorophenyl)methyl]-1-methyl-5-oxo-L-prolinamide; GTP, guanosine-5′-triphosphate; HEMADO, 2-(1-Hexynyl)-N-methyl adenosine; HENECA, 2-hexynyladenosine-59-N-ethylcarboxamide; IB-MECA, N6-(3-Iodobenzyl)-9-[5-(methylcarbamoyl)-β-D-ribofuranosyl]adenine; INS 365, [[[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]; INS 37217, P(1)-(uridine 5′)-P(4)- (2′-deoxycytidine 5′)tetraphosphate; INS48823, {[(3aR,4R,6R,6aR)-2-benzyl-6-(2,4-dioxo-1,2,3,4-tetra-hydropyrimidin-1-yl)-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methoxy}({[({[(2S,3R,4S,5S)-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy) phosphoryl)oxy](hydroxy)phosphoryl}oxy)phosphinic acid; INS50589, [(2S,3aR,4R,6R,6aR)-6-[6-(ethylcarbamoylamino)purin-9-yl]-2-[(E)-2-phenylethenyl]-3a,4,6,6a-tetrahydrofuro[4,3-d][1,3]dioxol-4-yl]methyl dihydrogen phosphate; IP5I, di-inosine pentaphosphate; isoPPADS, iso-pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid; JNJ-42253432, 2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide; JNJ-47965567, 2-(Phenylthio)-N-[[tetrahydro-4-(4-phenyl-1-piperazinyl)-2H-pyran-4-yl] methyl-3-pyridinecarboxamide; KF17837, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine; KN04, N-[1-[N-methyl-p-(5-isoquinolinesulphonyl)benzyl]-2-(4-phenylpiperazine) ethyl]-5-isoquinoline-sulfonamide; KN62, 1-[N,O-bis(5-Isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine; KW 6002, (E)-1,3-Diethyl-8-(3,4-dimethoxyphenylethyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione; L-α,β-meATP, L-α,β-methylene ATP; L-β,γ-meATP, L-β,γ-methylene ATP; 2′-MeCCPA, 2-chloro-N-cyclopentyl-2′-methyladenosine; 2-MeSADP, 2-methylthio ADP; 2-MeSAMP, 2-methylthio AMP; 2-MeSATP, 2-methylthio ATP; α,β-meUDP, α,β-methylene UDP; ≫, much greater affinity than; >, greater affinity than; ≥, greater or equal affinity than.