Is TL-99 a selective presynaptic dopamine receptor agonist?
The claim that the 2-aminotetralin analogue TL-99 is a selective presynaptic dopamine (DA) receptor agonist has been investigated both in vivo and in vitro in the rat. The pharmacological specificity of the hypomotility caused by TL-99 has been examined using various selective antagonists. In addition its effects on DA metabolism and noradrenaline (NA) and DA turnover (alpha-MT method) as well as its distribution in the brain have been studied. These in vivo studies provide evidence that although TL-99 is able to activate presynaptic DA receptors it is also a potent agonist of NA receptors as shown by the fact that the hypomotility could be partly reversed by the selective alpha 2-adrenoceptor antagonists yohimbine and piperoxan. Further supporting evidence for these findings was provided by in vitro studies on the inhibition of K+-induced [3H]dopamine, [14C]acetylcholine and [3H]noradrenaline release from striatal and cortical slices where it was shown that TL-99 is not only active at both pre- and postsynaptic DA receptors but also at alpha 2-NA receptors. For the latter receptor it had a potency comparable to that of the potent alpha 2-agonist clonidine and this may explain, to some extent, the hypomotility caused by TL-99. Thus, ascribing this hypomotility solely to an interaction with presynaptic DA receptors may be an oversimplification. It is therefore concluded that TL-99 should not be considered as a selective presynaptic DA receptor agonist.
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005476:Fluphenazine / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013134:Spiperone / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013997:Time Factors
D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D013134:Spiperone; C016893:2-(N,N-dimethylamino)-6,7-dihydroxytetralin; D000109:Acetylcholine; D005476:Fluphenazine; D004298:Dopamine; D009638:Norepinephrine