Molecular modelling of UH-301 and 5-HT(1a) receptor interactions.
A three-dimensional model of the human 5-HT(1a) receptor was constructed by molecular modelling, and the molecular and electronic structures of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin (UH-301) and of (R)- and (S)-8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) were examined by molecular mechanics and quantum mechanics calculations and molecular dynamics simulations. The receptor model has seven transmembrane alpha-helices (TMHs), organized according to a projection map of visual rhodopsin, and includes all loops between helices and the N- and C-terminal parts. Interactions of UH-301 and 8-OH-DPAT with the 5-HT(1a) receptor were examined by molecular dynamics simulations and energy minimization of receptor-ligand complexes. 8-OH-DPAT had lower electrostatic potentials around the hydroxyl group and stronger hydrogen bonding to the receptor model than had UH-301. The simulations indicated that the 5-HT(1a) receptor agonists, (R)- and (S)-8-OH-DPAT and (R)-UH-301, interacted with the receptor at a site closer to Asp82 in TMH2 than did (S)-UH-301, which is a 5-HT1a receptor antagonist. Simulations of receptor-ligand complexes indicated that Asp82, Asp116, Serl99, Thr2OO and Ile385 are essential for binding of both agonist and antagonist to the receptor.
Sylte
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Department of Pharmacology. Institute of Medical Biology, University of Tromsø, Norway.
Edvardsen
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Dahl
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D018491:Dopamine Agonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011985:Receptors, Serotonin / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D018491:Dopamine Agonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; C064282:UH 301; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C031349:7-hydroxy-2-N,N-dipropylaminotetralin