Serotonin Dimers:  Application of the Bivalent Ligand Approach to the Design of New Potent and Selective 5-HT_1B/1D Agonists

Abstract

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.

Evidence for a Multivalent Interaction of Symmetrical, N-Linked, Lidocaine Dimers with Voltage-Gated Na+ Channels

“…Bivalent ligand design has been used successfully for such G-protein-coupled receptors as ␤-adrenergic (Kizuka and Hanson, 1987), opioid (Portoghese et al, 1988), muscarinic acetylcholine (Christopoulos et al, 2001), 5-HT 1A/D (LeBoulluec et al, 1995) and 5-HT 1B/1D (Halazy et al, 1996) receptors. Similar studies have also been undertaken for voltagegated calcium channels (Joslyn et al, 1988) and SK Ca (Galanakis et al, 1996), nicotinic (Rosini et al, 1999), and cyclic nucleotide-gated (Kramer and Karpen, 1998) ion channels.…”

Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

“…There are several papers describing the "bivalent ligand" approach, which have performed good results in terms of affinity and selectivity, [18][19][20][21] and to the best of our knowledge, in the field of the 5-HT 7 /5-HT 1A receptor ligands it was used only once before. 22 Given the importance of the 1-arylpiperazine moiety for its affinity to serotoninergic receptors, we have duplicated this template in order to identify homo and hetero bis-piperazine 5-HT 7 R selective ligands.…”

Design, Synthesis, and Pharmacology of Fluorescently Labeled Analogs of Serotonin: Application to Screening of the 5-HT2C Receptor

“…to a solution of 10 mg of amine 3a 10 (31 µmol) in 5 mL dichloromethane (DcM) was added 3.0 µL (32 µmol) acetic anhydride and 5 µL diisopropylethylamine (DIeA). After 20 min, the reaction mixture was quenched with 5 µL ethanolamine and evaporated.…”