Probing the steric space at the floor of the D1 dopamine receptor orthosteric binding domain: 7α-, 7β-, 8α-, and 8β-methyl substituted dihydrexidine analogues.
ABSTRACT To probe the space at the floor of the orthosteric ligand binding site in the dopamine D(1) receptor, four methylated analogues of dihydrexidine (DHX) were synthesized with substitutions at the 7 and 8 positions. The 8α-axial, 8β-equatorial, and 7α-equatorial were synthesized by photochemical cyclization of appropriately substituted N-benzoyl enamines, and the 7β-axial analogue was prepared by an intramolecular Henry reaction. All of the methylated analogues displayed losses in affinity when compared to DHX (20 nM): 8β-Me(ax)-DHX (270 nM), 8α-Me(eq)-DHX (920 nM), 7β-Me(eq)-DHX (6540 nM), and 7α-Me(ax)-DHX (>10000 nM). Molecular modeling studies suggest that although the disruption of an aromatic interaction between Phe203(5.47) and Phe288(6.51) is the cause for the 14-fold loss in affinity associated with 8β-axial substitution, unfavorable steric interactions with Ser107(3.36) result in the more dramatic decreases in binding affinity suffered by the rest of the analogues.
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ABSTRACT: We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching.Journal of Computational Chemistry 08/2004; 25(9):1157-74. · 4.58 Impact Factor
Article: Serine mutations in transmembrane V of the dopamine D1 receptor affect ligand interactions and receptor activation.[show abstract] [hide abstract]
ABSTRACT: Several serines present in transmembrane domain V are conserved among members of the G-protein-coupled receptor family that bind catecholamines. Two of these serines that are present in the beta-adrenergic receptor were previously shown by site-directed mutagenesis to affect agonist binding and receptor activation (Strader, C. D., Candelore, M. R., Hill, W. S., Sigal, I. S., and Dixon, R. A. F. (1989) J. Biol. Chem. 264, 13572-13578). We investigated the role of the serines present in transmembrane V of another catecholamine receptor, the dopamine D1 receptor, by site-directed mutagenesis, and the results show that mutations at serines 198, 199, and 202 affect dopamine binding. The substitution of serine 198 or serine 199 by an alanine also affects the binding of several other agonist and antagonist dopaminergic compounds while an alanine substitution at serine 202 has no effect on the binding of these compounds. Moreover, each single serine mutation decreased the maximal cAMP accumulation elicited by a dopamine D1 partial agonist. These results suggest that serines present in transmembrane V of the D1 receptor affect ligand interactions and receptor signal transduction, but not entirely in the manner that would be predicted from the model proposed for the beta-adrenergic receptor.Journal of Biological Chemistry 10/1992; 267(25):17780-6. · 4.77 Impact Factor
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ABSTRACT: The results of INDO calculations on dopamine are reported. A conformational energy map and an isodistance map for the key distances N-OH1, N-OH2 in dopamine as functions of the two main torsion angles tau1 and tau2 were constructed. In addition to the three known minima of dopamine corresponding to the trans and gauche forms, two new minima were found. The key distances of the rigid analogues of dopamine, apomorphine, isoapomorphine, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene and isoquinoline were plotted on the isodistance map of dopamine. By taking the corresponding tau values as coordinates on the energy map, conformations of dopamine, resembling the rigid analogues, could be found. When a conformation is close to a local minimum it is assumed that this conformation is energetically favourable. The possible relation between the energy minima and the biological action of dopamine is discussed. An explanation is suggested for the lack of dopaminergic activity of isoapomorphine.Journal of Pharmacy and Pharmacology 04/1977; 29(3):153-6. · 2.17 Impact Factor