Thiophene analogs of naphthoxazines and 2-aminotetralins: bioisosteres with improved relative oral bioavailability, as compared to 5-OH-DPAT.
In the present study, a series of thiophene analogs of 2-aminotetralins and hexahydronaphthoxazines were studied in vivo for their ability to decrease striatal dopamine release, their effects on locomotor activity, and their behavioral characteristics in reserpinized rats, in order to investigate whether a thiophene moiety can act as a bioisostere for the phenol moiety. In general, the new compounds showed lower in vivo activities than 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT). However, the introduction of the thiophene moiety gave a significant improvement of the relative oral bioavailability, compared to 5-OH-DPAT. Our results suggest that the thiophene moiety can act as a bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the thianaphthoxazines it was not possible to discriminate between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenzo[b]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability.
Rodenhuis
N
N
Department of Medicinal Chemistry, University Centre for Pharmacy, University of Groningen, A. Deusinglaan 1, NL-9713 AV, Groningen, The Netherlands.
Timmerman
W
W
Wikström
H V
HV
Dijkstra
D
D
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001682:Biological Availability; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
C493595:Drd3 protein, rat; D009281:Naphthalenes; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D013565:Sympatholytics; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C011799:5-hydroxy-2-N,N-dipropylaminotetralin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine