TY - JOUR T1 - Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine<sub>1a</sub> Receptor Ligands to Explore the Three-Dimensional Structure of the Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 15 LP - 21 DO - 10.1124/mol.62.1.15 VL - 62 IS - 1 AU - Marı́a L. López-Rodrı́guez AU - Bruno Vicente AU - Xavier Deupi AU - Sergio Barrondo AU - Mireia Olivella AU - M. José Morcillo AU - Bellinda Behamú AU - Juan A. Ballesteros AU - Joan Sallés AU - Leonardo Pardo Y1 - 2002/07/01 UR - http://molpharm.aspetjournals.org/content/62/1/15.abstract N2 - In this work, we evaluate the structural differences of transmembrane helix 3 in rhodopsin and the 5-hydroxytryptamine 1A (5-HT1A) receptor caused by their different amino acid sequence. Molecular dynamics simulations of helix 3 in the 5-HT1A receptor tends to bend toward helix 5, in sharp contrast to helix 3 in rhodopsin, which is properly located within the position observed in the crystal structure. The relocation of the central helix 3 in the helical bundle facilitates the experimentally derived interactions between the neurotransmitters and the Asp residue in helix 3 and the Ser/Thr residues in helix 5. The different amino acid sequence that forms helix 3 in rhodopsin (basically the conserved Gly3.36Glu3.37 motif in the opsin family) and the 5-HT1A receptor (the conserved Cys3.36Thr3.37 motif in the neurotransmitter family) produces these structural divergences. These structural differences were experimentally checked by designing and testing ligands that contain comparable functional groups but at different interatomic distance. We have estimated the position of helix 3 relative to the other helices by systematically changing the distance between the functional groups of the ligands (1 and2) that interact with the residues in the receptor. Thus, ligand 1 optimally interacts with a model of the 5-HT1A receptor that matches rhodopsin template, whereas ligand 2 optimally interacts with a model that possesses the proposed conformation of helix 3. The lack of affinity of1 (K i &gt; 10,000 nM) and the high affinity of 2 (K i = 24 nM) for the 5-HT1A receptor binding sites, provide experimental support to the proposed structural divergences of helix 3 between the 5-HT1A receptor and rhodopsin. ER -