Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is aprotein that in humans is encoded by the DRD1 gene.[5][6][7][8]
D1 receptors regulate thememory,learning, and the growth ofneurons, also is used in the reward system and locomotor activity, mediating some behaviors and modulatingdopamine receptor D2-mediated events.[11][8]
There are a number of ligands selective for the D1 receptors. To date, most of the known ligands are based ondihydrexidine or the prototypicalbenzazepine partial agonistSKF-38393 (one derivative being the prototypical antagonistSCH-23390).[12] D1 receptor has a high degree ofstructural homology to another dopamine receptor,D5, and they both bind similar drugs.[13] As a result, none of the known orthosteric ligands is selective for the D1 vs. the D5 receptor, but the benzazepines generally are more selective for the D1 and D5 receptors versus the D2-like family.[12] Some of the benzazepines have high intrinsic activity whereas others do not. In 2015 the firstpositive allosteric modulator for the human D1 receptor was discovered byhigh-throughput screening.[14]
Chemical structures of selective D1 receptor agonists[15][16]
Several D1 receptor agonists are used clinically. These includeapomorphine,pergolide,rotigotine, andterguride. All of these drugs are preferentiallyD2-like receptor agonists.Fenoldopam is a selective D1 receptorpartial agonist that does not cross theblood-brain-barrier and is usedintravenously in the treatment ofhypertension.Dihydrexidine andadrogolide (ABT-431) (aprodrug ofA-86929 with improvedbioavailability) are the only selective, centrally activeD1-like receptor agonists that have been studied clinically in humans.[17] The selective D1 agonists give profound antiparkinson effects in humans and primate models of PD, and yield cognitive enhancement in many preclinical models and a few clinical trials. The most dose-limiting feature is profoundhypotension, but the clinical development was impeded largely by lack of oral bioavailability and short duration of action.[17][18][19] In 2017, Pfizer made public information about pharmaceutically-acceptable non-catechol selective D1 agonists that are in clinical development.
A-86929 – full agonist with 14-fold selectivity for D1-like receptors over D2[12][16][20]
Dihydrexidine – full agonist with 10-fold selectivity for D1-like receptors over D2 that has been in Phase IIa clinical trials as a cognitive enhancer.[21][22] It also showed profound antiparkinson effects in MPTP-treated primates,[23] but caused profound hypotension in one early clinical trial inParkinson's disease.[12] Althoughdihydrexidine has significant D2 properties, it is highly biased at D1 receptors and was used for the first demonstration offunctional selectivity[24] with dopamine receptors.[25][26]
Dinapsoline – full agonist with 5-fold selectivity for D1-like receptors over D2[12]
Dinoxyline – full agonist with approximately equal affinity for D1-like and D2 receptors[12]
Doxanthrine – full agonist with 168-fold selectivity for D1-like receptors over D2[12]
Benzazepine derivatives
SKF-81297 – 200-fold selectivity for D1 over any other receptor[12]
CY-208,243 – high intrinsic activity partial agonist with moderate selectivity for D1-like over D2-like receptors, member ofergoline ligand family likepergolide andbromocriptine.
SKF-89145
SKF-89626
7,8-Dihydroxy-5-phenyl-octahydrobenzo[h]isoquinoline – extremely potent, high-affinity full agonist[28]
Cabergoline – weak D1 agonism, highly selective for D2, and various serotonin receptors
Pergolide – (similar to cabergoline) weak D1 agonism, highly selective for D2, and various serotonin receptors
Aphotoswitchable agonist of D1-like receptors (azodopa[29]) has been described that allows reversible control of dopaminergic transmission in wildtype animals.
Manytypical andatypical antipsychotics are D1 receptor antagonists in addition to D2 receptor antagonists. Butasenapine has shown stronger D1 receptor affinity compared to other antipsychotics. No other D1 receptor antagonists have been approved for clinical use.Ecopipam is a selective D1-like receptor antagonist that has been studied clinically in humans in the treatment of a variety of conditions, includingschizophrenia,cocaine abuse,obesity,pathological gambling, andTourette's syndrome, withefficacy in some of these conditions seen. The drug produced mild-to-moderate, reversibledepression andanxiety in clinical studies however and has yet to complete development for any indication.
Ecopipam (SCH-39,166) – a selective D1/D5 antagonist that was being developed as ananti-obesity medication but was discontinued[12] However, it has showed promise in reducingstuttering and is currently in Phase 2 Trials for this purpose[34][35]
SeveralCryoEM structures of agonists bound to the dopamine D1 receptor complexed with the stimulatory heterotrimeric Gs protein have been determined. Agonist interact with extracellular loop 2 and extracellular regions of trans-membrane helices 2, 3, 6, and 7. Interactions between catechol-based agonists and three trans-membrane serine residues including S1985.42, S1995.43, and S2025.46 function as microswitches that are essential for receptor activation.[43]
Dopamine D1 CryoEM structure in complex with dopamine (PDB code: 7LJD), Dopamine D1 receptor in orange, dopamine in cyan, interactions are in green.[44]
^Zhou QY, Grandy DK, Thambi L, Kushner JA, Van Tol HH, Cone R, Pribnow D, Salon J, Bunzow JR, Civelli O (September 1990). "Cloning and expression of human and rat D1 dopamine receptors".Nature.347 (6288):76–80.Bibcode:1990Natur.347...76Z.doi:10.1038/347076a0.PMID2168520.S2CID4313577.
^Sunahara RK, Niznik HB, Weiner DM, Stormann TM, Brann MR, Kennedy JL, Gelernter JE, Rozmahel R, Yang YL, Israel Y (September 1990). "Human dopamine D1 receptor encoded by an intronless gene on chromosome 5".Nature.347 (6288):80–83.Bibcode:1990Natur.347...80S.doi:10.1038/347080a0.PMID1975640.S2CID4236625.
^abSchetz JA, Sibley DR (2007). "Chapter 7: Dopaminergic Neurotransmission". In Sibley DR (ed.).Handbook of Contemporary Neuropharmacology. Hoboken, NJ: Wiley-Interscience. p. 226.ISBN9780471660538.Localization of the D1 receptor messenger ribonucleic acid (mRNA) expression has been mapped using Northern analysis and in situ hybridization (for a review, see [54]). Expression of D1 receptor mRNA is highest in the caudate putamen, nucleus accumbens, and olfactory tubercle. Lower levels of expression are found in the basolateral amygdala, cerebral cortex,septum pellucidum, thalamus, and hypothalamus.
^Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB (April 1991). "Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1".Nature.350 (6319):614–619.Bibcode:1991Natur.350..614S.doi:10.1038/350614a0.PMID1826762.S2CID4373022.
^Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE (November 2006). "trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist".Journal of Medicinal Chemistry.49 (23):6848–6857.doi:10.1021/jm0604979.PMID17154515.
^abMichaelides MR, Hong Y, DiDomenico S, Asin KE, Britton DR, Lin CW, Williams M, Shiosaki K (September 1995). "(5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1- ena[c]-phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintains behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)".Journal of Medicinal Chemistry.38 (18):3445–3447.doi:10.1021/jm00018a002.PMID7658429.
^Yamashita M, Yamada K, Tomioka K (February 2004). "Construction of arene-fused-piperidine motifs by asymmetric addition of 2-trityloxymethylaryllithiums to nitroalkenes: the asymmetric synthesis of a dopamine D1 full agonist, A-86929".Journal of the American Chemical Society.126 (7):1954–1955.doi:10.1021/ja031760n.PMID14971926.
^Mu Q, Johnson K, Morgan PS, Grenesko EL, Molnar CE, Anderson B, Nahas Z, Kozel FA, Kose S, Knable M, Fernandes P, Nichols DE, Mailman RB, George MS (August 2007). "A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia".Schizophrenia Research.94 (1–3):332–341.doi:10.1016/j.schres.2007.03.033.PMID17596915.S2CID25497605.
^George MS, Molnar CE, Grenesko EL, Anderson B, Mu Q, Johnson K, Nahas Z, Knable M, Fernandes P, Juncos J, Huang X, Nichols DE, Mailman RB (July 2007). "A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia".Schizophrenia Research.93 (1–3):42–50.doi:10.1016/j.schres.2007.03.011.PMID17467956.S2CID31375175.
^Mottola DM, Kilts JD, Lewis MM, Connery HS, Walker QD, Jones SR, Booth RG, Hyslop DK, Piercey M, Wightman RM, Lawler CP, Nichols DE, Mailman RB (June 2002). "Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase".The Journal of Pharmacology and Experimental Therapeutics.301 (3):1166–1178.doi:10.1124/jpet.301.3.1166.PMID12023552.S2CID2858428.
^Kilts JD, Connery HS, Arrington EG, Lewis MM, Lawler CP, Oxford GS, O'Malley KL, Todd RD, Blake BL, Nichols DE, Mailman RB (June 2002). "Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs".The Journal of Pharmacology and Experimental Therapeutics.301 (3):1179–1189.doi:10.1124/jpet.301.3.1179.PMID12023553.
^abBermak JC, Li M, Bullock C, Weingarten P, Zhou QY (February 2002). "Interaction of gamma-COP with a transport motif in the D1 receptor C-terminus".European Journal of Cell Biology.81 (2):77–85.doi:10.1078/0171-9335-00222.PMID11893085.
^Bermak JC, Li M, Bullock C, Zhou QY (May 2001). "Regulation of transport of the dopamine D1 receptor by a new membrane-associated ER protein".Nature Cell Biology.3 (5):492–498.doi:10.1038/35074561.PMID11331877.S2CID40809366.
^Juhasz JR, Hasbi A, Rashid AJ, So CH, George SR, O'Dowd BF (March 2008). "Mu-opioid receptor heterooligomer formation with the dopamine D1 receptor as directly visualized in living cells".European Journal of Pharmacology.581 (3):235–243.doi:10.1016/j.ejphar.2007.11.060.PMID18237729.
"Dopamine Receptors: D1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2015-01-02. Retrieved2008-12-04.
