ABSTRACT
New dimers of known 5HT1 ligands (5HT, 1-NP or 8-OH-DPAT) have been prepared and evaluated at human cloned 5HT1B, 5HT1D and 5HT1A receptors. Binding experiments show that all these dimers have better affinities at 5HT1B/1D receptors than their corresponding monomeric ligands. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5HT1B receptor show that hetero-bivalent ligands [combining an agonist (5HT) with an antagonist (1-NP)] behave as partial agonists while the intrinsic activity of bivalent antagonists (combining two 1-NP residues) was found to be spacer dependent. Surprisingly enough, the dimer of 8-OH-DPAT 6 binds to 5HT1A, 5HT1B and 5HT1D receptors with similar high affinity.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Agents/chemical synthesis , 8-Hydroxy-2-(di-n-propylamino)tetralin/analogs & derivatives , 8-Hydroxy-2-(di-n-propylamino)tetralin/chemistry , 8-Hydroxy-2-(di-n-propylamino)tetralin/metabolism , Cyclic AMP/antagonists & inhibitors , Humans , Ligands , Piperazines/chemistry , Piperazines/metabolism , Radioligand Assay , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin, 5-HT1 , Recombinant Proteins/metabolism , Serotonin/analogs & derivatives , Serotonin/chemistry , Serotonin/metabolism , Serotonin Agents/chemistry , Serotonin Agents/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolismABSTRACT
A series of serotonin dimers of formula 4 in which two serotonin moeities are linked together through their 5-hydroxyl residue has been prepared and evaluated as 5-HT(1B/1D) receptor agonists. Binding experiments at cloned human 5-HT(1B), 5-HT(1D), and 5-HT(1A) receptors show that all of these dimers are very potent ligands at 5-HT(1B/1D) receptors with increased binding selectivity vs the 5-HT(1A) receptor when compared to serotonin. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5-HT(1B) receptor (formerly the 5-HT(1Dbeta) receptor) demonstrate that all of these serotonin dimers behave as full agonists. Among them, the piperazide derivatives of bis-serotonin, 4g,j, were also identified as very potent agonists in contracting the New Zealand white rabbit saphenous vein (pD2 = 7.6 in each case compared to 5.8 for sumatriptan). Results analysis supports the hypothesis that the important increase in potency of the serotonin dimers can be attributed to the presence of two serotonin pharmacophores in the same molecule, while the enhanced selectivity for 5-HT(1B/1D) receptor subtypes may be due to the position of the spacer attachment to serotonin.
