Structural factors of importance for 5-hydroxytryptaminergic activity. Conformational preferences and electrostatic potentials of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and some related agents.
The conformational characteristics of two series of 5-hydroxytryptamine (5-HT) receptor agonists, monophenolic N,N-dialkylated 2-aminotetralins and trans-2-phenylcyclopropylamines, have been studied by a combination of experimental (NMR spectroscopy) and theoretical (molecular mechanics and MNDO calculations) methods. In addition, molecular electrostatic potentials have been calculated for selected conformations and the absolute configuration of the potent 5-HT-receptor agonist (+)-cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin has been determined, by X-ray crystallography of the synthetic precursor, to be 1S,2R. Results obtained are discussed in terms of conformational, steric, and electronic requirements for 5-HT-receptor activation. It is suggested that different conformations of the 5-HT-receptor agonists (1R,2S)-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine [(1R,2S)-4] and its 3-hydroxy isomer (1R,2S)-5 are able to activate 5-HT receptors. The strongly increased stereoselectivity of 2, 4, and 5 as compared to that of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1) is rationalized on the basis of steric factors. Conformational factors appear to be responsible for the inability of the trans-C1-methyl-substituted derivative of 1 to activate 5-HT receptors.
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004563:Electrochemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014961:X-Ray Diffraction
D009281:Naphthalenes; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin