7-Hydroxy-DPAT hydrobromide

Aminotetralin drugs and D3 receptor functions. What may partially selective D3 receptor ligands tell us about dopamine D3 receptor functions?[Pubmed:8759022]

Biochem Pharmacol. 1996 Aug 23;52(4):511-8.

The dopamine D3 receptor gene was identified by Sokoloff and colleagues in 1990. This finding rapidly gained the interest of the scientific community because this unexpected dopamine receptor subtype may play an important role in the antipsychotic activity of neuroleptic drugs. It recognizes most neuroleptics with a high affinity, and its brain distribution is restricted mainly to the ventral part of the striatal complex. However, the characterization and the subsequent identification of functions of the D3 receptor were hampered initially by at least four important factors that are still partially unresolved: (1) the absence of selective drugs that can discriminate between the D2 and D3 receptor subtype functions in vivo, (2) the lack of apparent coupling with GTP-dependent proteins, (3) the absence of effects on second messenger systems, and (4) the low level of expression of this receptor in brain tissue; these factors have contributed to tempering the interest of scientists. However, this situation has begun to change with the identification of [3H]7-hydroxy-N,N-(di-n-propyl)-2-aminotetralin ([3H]7-OH-DPAT), the first selective ligand for the dopamine D3 receptor. Although its binding selectivity for the D3 versus the D2 receptor is somewhat artificial, the potentially important impact of identification of a function for the D3 receptor encouraged scientists to use this aminotetralin compound for in vivo studies with, however, limited success. This commentary is focused on the impact and controversies generated by the use of 7-OH-DPAT and its congeners, on new conceptual views that may arise from this research, and on what partially selective D3 receptor ligands may tell us about dopamine D3 receptor functions.

Dopamine receptor pharmacology.[Pubmed:7940991]

Trends Pharmacol Sci. 1994 Jul;15(7):264-70.

Dopamine receptors are the primary targets in the treatment of schizophrenia, Parkinson's disease, and Huntington's chorea, and are discussed in this review by Philip Seeman and Hubert Van Tol. Improved therapy may be obtained by drugs that selectively target a particular subtype of dopamine receptor. Most antipsychotic drugs block D2 receptors in direct correlation to clinical potency, except clozapine, which prefers D4 receptors. D1 and D2 receptors can enhance each other's actions, possibly through subunits of the G proteins. In schizophrenia, the D2 and D3 receptor density is elevated by 10%, while the D4 receptor density is elevated by 600%. Therefore, D4 receptors may be a target for future antipsychotic drugs. While antipsychotics originally helped to discover dopamine receptors, the five cloned dopamine receptors are now facilitating the discovery of selective antipsychotic and antiparkinson drugs.

Behavioural effects of the putative D-3 dopamine receptor agonist 7-OH-DPAT in relation to other "D-2-like" agonists.[Pubmed:8321432]

Neuropharmacology. 1993 May;32(5):509-10.

The putative D-3 dopamine receptor agonist 7-OH-DPAT (10 micrograms/kg, s.c.) reduced spontaneous activity in rats, without inducing yawning; higher doses (0.1-10.0 mg/kg, s.c.) stimulated non-stereotyped sniffing, locomotion and chewing, which were attenuated by the selective D-1 antagonist BW 737C (5.0 mg/kg, s.c.) without release of any atypical behaviours. Low doses of 7-OH-DPAT may act on inhibitory D-3 receptors, while higher doses may act at stimulatory D-3 or other "D-2-like" receptors that participate in cooperative but not oppositional interactions with D-1 receptors.

Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin.[Pubmed:1518841]

Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8155-9.

We have identified 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin ([3H]7-OH-DPAT) as a selective probe for the recently cloned dopamine D3 receptor and used it to assess the presence of this receptor and establish its distribution and properties in brain. In transfected Chinese hamster ovary (CHO) cells, it binds to D3 receptors with subnanomolar affinity, whereas its affinity is approximately 100-, 1000-, and 10,000-fold lower at D2, D4, and D1 receptors, respectively. Specific [3H]7-OH-DPAT binding sites, with a Kd of 0.8 nM and a pharmacology similar to those at reference D3 receptors of CHO cells, were identified in rat brain. D3 receptors differ from D2 receptors in brain by their lower abundance (2 orders of magnitude) and distribution, restricted to a few mainly phylogenetically ancient areas--e.g., paleostriatum and archicerebellum--as evidenced by membrane binding are autoradiography studies. Native D3 receptors in brain are characterized by an unusually high nanomolar affinity for dopamine and a low modulatory influence of guanyl nucleotides on agonist binding. These various features suggest that D3 receptors are involved in a peculiar mode of neurotransmission in a restricted subpopulation of dopamine neurons.