Molecular modeling of the dopamine D-2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-OMe-BPAT

Molecular modeling studies were undertaken in order to elucidate the possib le dopamine D-2 and serotonin 5-HT1A receptor binding modes of the enantiom ers of 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-pylamino]tetralin (5-OMe-BPAT, 1). For this purpose, a combination of indirect molecular modeling and dir ect construction of the seven transmembrane (7TM) domains of the receptors was employed in a stepwise, objective manner. Pharmacophore models and corr esponding receptor maps were identified by superimposing selected sets of r eceptor agonists in their presumed pharmacologically active conformations, while taking the conformational freedom of the ligands into account. The 7T M models were then constructed around the agonist pharmacophore models, by adding the TM domains one-by-one. Initially, the relative positions of TM3, TM4, and TM5 were determined using the three-dimensional structure of bact eriorhodopsin, but subsequently the orientations of all TM domains were adj usted in order to mimic the topology of the TM domains of rhodopsin. The pr esumed dopamine D2 receptor binding conformations of(S)- and (R)-1 were det ermined by using the semirigid dopamine D2 receptor antagonist N-benzylpiqu indone as a template for superposition. Similarly, the selective serotonin 5-HT1A receptor agonist flesinoxan was employed for identifying the seroton in 5-HT1A receptor binding conformations of the enantiomers of 1. After doc king of the presumed pharmacologically active conformations in the 7TM mode ls and subsequent optimization of the binding sites, specific interactions between the ligands and the surrounding amino acid residues, consistent wit h the structure-activity relationships, were observed. Thus, both enantiome rs of 1 bound to the dopamine D-2 receptor model in a similar fashion: a re inforced electrostatic interaction was present between the protonated nitro gen atoms and Asp114 in TM3; their carbonyl groups accepted a H-bond from S er121 in TM3; their amide NH groups acted as H-bond donor to Tyr416 in TM7; and their benzamide phenyl rings were involved in a hydrophobic edge-to-fa ce interaction with Trp386 in TM6. Differences were observed in the orienta tions of the 2-aminotetralin moieties, which occupied the agonist binding s ite. Whereas the (S)-enantiomer could form a H-bond between its 5-methoxy s ubstituent and Ser193 in TM5, the (R)-enantiomer could not, which may accou nt for the differences in their intrinsic efficacies at the dopamine D-2 re ceptor. In the serotonin 5-HT1A receptor model, the benzamide phenyl rings of both enantiomers were involved in hydrophobic face-to-face interactions with Phe112 in TM3, while their protonated nitrogen atoms formed a reinforc ed electrostatic interaction with Asp116 in TM3. Consistent with the struct ure-affinity relationships of 1, the amide moieties were not involved in sp ecific interactions. Both enantiomers of 1 could form a hydrogen bond betwe en their 5-methoxy substituent and Thr200 in TM5, which may account for the ir full serotonin 5-HT1A receptor agonist properties. (C) 1999 Elsevier Sci ence Ltd. All rights reserved.