title: Derivatives of 2-(dipropylamino)tetralin: effect of the C8-substituent on the interaction with 5-HT1A receptors.
abstract: A series of 2-(dipropylamino)tetralin derivatives in which the C8 substituent is varied has been prepared and evaluated pharmacologically to explore the importance of the C8 substituent in the interaction of 2-aminotetralin-based ligands with serotonin (5-HT1A) receptors. Enantiopure derivatives were prepared by facile palladium-catalyzed reactions of the triflates of the enantiomers of 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 1). The affinity of the compounds for the 5-HT1A receptors was evaluated by competition experiments with [3H]-8-OH-DPAT in rat hippocampal and cortical tissue. In addition, the compounds were evaluated for central 5-HT and dopamine receptor stimulating activity in vivo by use of biochemical and behavioral assays in rats. With the exception of the carboxy-substituted derivative which is devoid of 5-HT1A receptor affinity, the compounds have moderate to high affinities (K(i) values range from 0.7 to 130 nM) for 5-HT1A receptors. Surprisingly, several of the derivatives do not produce any apparent effects in vivo although they have fairly high 5-HT1A receptor affinities. However, the methoxycarbonyl- and acetyl-substituted derivatives are potent 5-HT1A receptor agonists in vivo and exhibit in vitro affinities in the same range as the enantiomers of 1.
authors.affiliation: Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: B E
authors.initials: BE
authors.lastname: Svensson
authors.forename: L
authors.initials: L
authors.lastname: Cortizo
authors.forename: T
authors.initials: T
authors.lastname: Lewander
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D011985:Receptors, Serotonin; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004295:Dihydroxyphenylalanine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine; D006916:5-Hydroxytryptophan; D004298:Dopamine