Dopamine D3-receptor agonist

Lamas X., Negus S., Nader M., Mello N. Effects of the putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline. Psychopharmacology. 124 306, 1996. 

Pilla M., Perachon S., Sautel F. et al. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature. 400 371, 1999. 

Akunne HC, Towers P, Ellis GJ, Dijkstra D, Wikstrom H, Heffner TG, Wise LD, Pugsley TA (1995) Characterization of binding of [3H]PD 128907, a selective dopamine D3 receptor agonist ligand, to CHO-K1 cells. Life Sci 57 1401-1410. 

Other studies indicate that the dopamine D3 receptor is located postsynaptically and is involved in locomotor activity and behaviour. Experiments with dopamine D3 receptor agonists and antagonists show that these receptors have inhibitory effects on locomotor activity and behaviour. In the literature it is also described that administration of dopamine D3 receptor antisense67 and dopamine D3 mutant mice77 give hyperactivity in the animals. Svensson et al 72,78 showed that the decrease in locomotor activity after agonist administration is not likely to be dependent upon effects on dopamine release or synthesis. 

Fink-Jensen, A. Nielsen, E.B. Hansen, L. Scheideler, M.A. (1998) Behavioral and neurochemical effects of the preferential dopamine D3 receptor agonist cis-8-OH-PBZI. Eur. J. Pharmacol. 342, 153-161. 

Spealman, R.D. (1996) Dopamine D3 receptor agonists partially reproduce the discriminative stimulus effects of cocaine in squirrel monkeys. J. Pharmacol. Exp. Ther. 278, 1128-1137. 

BP-897 Bioproject (France) Naphthalene carboxamide derivative Dopamine D3 receptor agonist... 

Lober, S., Hubner, H., Gmeiner, P. Fused azaindole derivatives molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725. Bioorg. Med. Chem. Lett. 2002, 72(17), 2377-2380. 

Recent studies suggest that naturally occurring ergot alkaloids and their derivatives are dopamine D3 receptor agonists. It has been suggested that this regulation can be used in the treatment of schizophrenia. 

Ivanova B, Spitteler M. Functionalized ergot—alkaloids as potential dopamine D3 receptor agonists ftn-treatment of schizophrenia. J Mol Struct 2012 1029 106-18. 

Dopamine, and most of the known dopamine receptor agonists, binds with higher affinity to the dopamine D3 than to the dopamine D2 receptor. Due to the close homology between the dopamine D2 and D3 receptors, especially in the transmembrane domains (-80%), it is difficult to predict dopamine D2 versus dopamine D3 receptor selectivity based on receptor models. Malmberg et al.115 suggested that the observed dopamine D3 receptor selectivity may not be due to a single specific interaction but rather to a small difference in conformation between the dopamine D3 and D2 receptors. 

Some of these compounds have been studied by several research groups to elucidate their structure activity relationship for dopamine receptors.98,100,101,201,205,210 212 Initially, these studies identified S-(-)-5-hydroxy-2-(N,N-di-n-propylamino)tetralin (S-(-)-5-OH-DPAT, S-(-)-9) as the most potent monohydroxy 2-aminotetralin.98,100,205 Later S-(-)-5-hydroxy-2-(N- -propyl-N-2-thienylethylamino)tetralin (S-(-)-N-0437, S-(-)-31) was found to be an even more potent dopamine receptor agonist.201 Moreover, R-(+)-7-hydroxy-2-(N,N-di- -propylamino)tetralin (R-(+)-7-OH-DPAT, R-(+)-10) was later shown to have preference for the dopamine D3 receptor... 

In a series of tetrahydrobenzo[ ]thiophene analogues, we have identified novel selective dopamine D3 receptor agents, one of which displays a 100-fold selectivity over dopamine D2 receptors. These results provide information for the development of pharmacophoric models of the dopamine D2 and D3 receptor subtypes that can be used for the future development of selective agonists at these receptor subtypes. 

N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[/>]thiophene (34) this has led to compounds (65, 66, 67) with moderate to high affinity for the dopamine D3 receptor. However, the affinity for the dopamine D2 receptor was dramatically decreased. Therefore, these compounds showed a high selectivity for the dopamine D3 receptor. The introduction of 2-substituents in 5-(N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[/>]thiophene (35) gave compounds with low to no affinity for the dopamine D2 and D3 receptors. Surprisingly, because the parent compounds 34 and 35 show a comparable affinity for the dopamine receptors. An explanation could be that compounds 65, 66 and 67 are structurally comparable with the dopamine D3-preferring agonist... 

Current drug-based therapies for Parkinson s disease are palliative therapies, i.e. they relieve the symptoms, but do not cure the disease. One of the current and expanding therapies is treatment with dopamine D2/D3 receptor agonists. There are a number of such therapeutics, e.g. bromocriptine, pergolide, apomorphine, ropinirole, and pramipexole. 

Kreiss, D.S. Bergstrom, D.A. Gonzalez, A.M. Huang, K.X. Sibley, D.R. Walters, J.R. (1995) Dopamine receptor agonist potencies for inhibition of cell firing correlate with dopamine D3 receptor binding affinities. Eur. J. Pharmacol. 277, 209-214. 

Williams, M. Wright, S. Lloyd, G.K. (1997) Improved therapies for Parkinson s disease life beyond dopamine D2/D3 receptor agonists. TiPS 18, 307-310. 

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