A genetic-function-approximation-based QSAR model for the affinity of arylpiperazines toward α1 adrenoceptors

Journal of Chemical Information and Modeling

Volumn 46, Issue 3, 2006, Pages 1466-1478

  Maccari, Laura ^a,c   Magnani, Matteo ^a   Strappaghetti, Giovannella ^b   Corelli, Federico ^a   Botta, Maurizio ^a   Manetti, Fabrizio ^a  

^a UNIVERSITY OF SIENA   (Italy)

^b UNIVERSITY OF PERUGIA   (Italy)

^c Seinabiotech SPA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

APPROXIMATION THEORY; DERIVATIVES; FUNCTION EVALUATION; HYDROGEN BONDS; ORGANIC COMPOUNDS;

GENETIC FUNCTION APPROXIMATION (GFA); QSAR MODEL; ROTATABLE BONDS; STRUCTURAL PROPERTIES;

STRUCTURE (COMPOSITION);

ALPHA 1 ADRENERGIC RECEPTOR; PIPERAZINE DERIVATIVE;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECT; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

MODELS, MOLECULAR; PIPERAZINES; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RECEPTORS, ADRENERGIC, ALPHA-1;

EID: 33745360143     PISSN: 15499596     EISSN: 1549960X     Source Type: Journal    
DOI: 10.1021/ci060031z     Document Type: Article

References (60)

1. Langer, S. Z. Presynaptic Regulation of Catecholamine Release. Biochem. Pharmacol. 1974, 23, 1793-1800.
2. Wood, C. L.; Arnett, C. D.; Clarke, W. R.; Tsai, B. S.; Lefkowitz, R. J. Subclassification of α-Adrenergic Receptors by Direct Binding Studies. Biochem. Pharmacol. 1979, 28, 1277-1282.
3. Hoffman, B. B.; Lefkowitz, R. J. α-Adrenergic Receptor Subtypes. N. Engl. J. Med. 1980, 302, 1390-1396.
4. 2-Adrenergic Receptor Antagonist, Suppresses Interleukin-1 and Increases Interleukin-10 Production Induced by Lipopolysaccharides. NeuroImmunoModulation 2002-2003, 10, 163-168.
5. 1- Adrenoceptor-Mediated Contraction of Isolated Rat Arteries. Fundam. Clin. Pharmacol. 2002, 16, 281-287.
6. 2-Adrenoceptors. BJU Int. 2000, 85, 959-961.
7. 2-Adrenoceptor Antagonist Activity. J. Med. Chem. 2000, 43, 3653-3664.
8. (e) Quaglia, W.; Pigini, M.; Tayebati, S. K.; Piergentili, A.; Giannella, M.; Marucci, G.; Melchiorre, C. Structure - Activity Relationships in 1,4-Benzodioxan-Related Compounds. 4. Effect of Aryl and Alkyl Substituents at Position 3 on α-Adrenoreceptor Blocking Activity. J. Med. Chem. 1993, 36, 1520-1528.
9. Strader, C. D.; Sigal, I. S.; Dixon, R. A. Structural Basis of β-Adrenergic Receptor Function. FASEB J. 1989, 3, 1825-1832.
10. Strader, C. D.; Sigal, I. S.; Dixon, R. A. Genetic Approaches to the Determination of Structure - Function Relationships of G Protein-Coupled Receptors. Trends Pharmacol. Sci. 1989, Dec. Suppl., 26-30.
11. 1A Adrenergic Receptor. J. Med. Chem. 2005, 48, 1088-1097.
12. 1d Adrenergic Receptor. J. Med. Chem. 2004, 47, 1900-1918.
13. 1A-Adrenoceptor Model in a Membrane Mimic. Biochem. Biophys. Res. Commun. 2004, 324, 916-921.
14. 1d-Adrenergic Receptor Activation: A Molecular Dynamics and Docking Study. Proteins 2001, 43, 382-394.
15. 1b-Adrenergic Receptor. Involvement of Basic and Hydrophobic Residues in Receptor Activation and G Protein Coupling. J. Biol. Chem. 2001, 276, 46485-46494.
16. 1-Adrenoceptor Selective Antagonists: Synthesis, Modeling, and Binding Studies. Bioorg. Med. Chem. 1998, 6, 925-935.
17. 1a-Adrenoceptor: Orientation and Function of Transmembrane Helix V Sidechains. Recept. Channels 1996, 4, 165-177.
18. (h) Fanelli, F.; De Benedetti, P. G. Computational Modeling Approaches to Structure - Function Analysis of G Protein-Coupled Receptors. Chem. Rev. 2005, 105, 3297-3351.
19. 1B-Adrenergic Receptor Involved in Agonist Binding: Differences in Docking Catecholamines to Receptor Subtypes. FEBS Lett. 1996, 399, 9-13.
20. 1b-Adrenergic Receptor Is Initiated by Disruption of an Interhelical Salt Bridge Constraint. J. Biol. Chem. 1996, 271, 28318-28323.
21. 1 Adrenergic Receptor; Ruffolo, R. R., Jr., Ed.; Humana Press: Clifton, NJ, 1987; pp 211-265.
22. 1-Adrenergic-Receptor Antagonists in the Treatment of Benign Prostatic Hyperplasia-Related Lower Urinary Tract Symptoms. Clin. Ther. 2004, 26, 1701-1713.
23. (b) Milani, S.; Djavan, B. Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Latest Update on α-Adrenoceptor Antagonists. BJU Int. 2005, 95, 29-36.
24. 1-Adrenergic Receptors and Their Inhibitors in Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. J. Urol. (Hagerstown, MD, U. S.) 2004, 171, 1029-1035.
25. Lowe, F. C. Treatment of Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Sexual Function. BJU Int. 2005, 95, 12-18.
26. (a) Steers, W. D.; Kirby, R. S. Clinical Ease of Using Doxazosin in BPH Patients with and without Hypertension. Prostate Cancer Prostatic Dis. 2005, 8, 152-157.
27. 1 Adrenoceptor Function in Health and Disease from Transgenic Animal Studies. Trends Endocrinol. Metab. 2003, 14, 107-113.
28. 1D-Adrenoceptor Subtypes. J. Pharmacol. Exp. Ther. 2003, 305, 1045-1053.
29. 2-Adrenergic Receptor Subtype Specificity of Intrathecally Administered Tizanidine Used for Analgesia for Neuropathic Pain. J. Neurosurg. 2004, 101, 641-647.
30. 2-Antagonist Yohimbine to Fluoxetine: Effects on Rate of Antidepressant Response. Neuropsychopharmacol. 2004, 29, 1166-1171.
31. 1A/B Adrenoceptor Subtype Selectivity in the Rat. Eur. Neuropsychopharmacol. 2005, 15, 231-234.
32. 2 Antagonist Mianserin to Ongoing Haloperidol Treatment in Drug-Resistant Chronically Hospitalized Schizophrenic Patients. Eur. Psychiatry 2000, 15, 388-390.
33. 2-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X. J. Pharmacol. Exp. Ther. 2003, 306, 646-657.
34. Catalyst, version 4.8; Accelrys, Inc.: San Diego, CA.
35. 2-Adrenoceptors. J. Med. Chem. 2001, 44, 2118-2132.
36. 1-Adrenoceptor Antagonists. 6. Structural Optimization of Pyridazinone-Arylpiperazines. Study of the Influence on Affinity and Selectivity of Cyclic Substituents at the Pyridazinone Ring and Alkoxy Groups at the Arylpiperazine Moiety. J. Med. Chem. 2003, 46, 3555-3558.
37. 1-Adrenoceptor Antagonists. 4. Pharmacophore-Based Design, Synthesis, and Biological Evaluation of New Imidazo-, Benzimidazo-, and Indoloarylpiperazine Derivatives. J. Med. Chem. 2002, 45, 3603-3611.
38. 1-Adrenoceptor Antagonists. Bioorg. Med. Chem. 2002, 10, 361-369.
39. 1- Adrenoceptor Binding Properties of New Arylpiperazine Derivatives Bearing a Flavone Nucleus as the Terminal Heterocyclic Molecular Portion. Bioorg. Med. Chem. 2004, 12, 1527-1535.
40. 1A Serotoninergic Receptors. Bioorg. Med. Chem. 2006, 14, 2828-2836.
41. 2-Adrenoceptors. J. Comput.-Aided Mol. Des. 2004, 18, 495-509.
42. As an example, some of the arylpiperazines under study are characterized by molecular portions exceeding the pharmacophoric model. They occupy regions of space where any feature of the model lies, and thus, they are not accounted by the model itself. However, such portions could be involved in steric clashes with the receptor counterpart. Such a limitation of the pharmacophoric modeling approach has been, in part, overcome with the introduction of the use of excluded volumes in Catalyst that supposes the (partial) knowledge of the ligand binding site to be applied.
43. Cerius2, version 4.8; Accelrys Inc.: San Diego, CA.
44. Minitab; Minitab Inc.: State College, PA, 2003.
45. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMm: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations. J. Comput. Chem. 1983, 4, 187-217.
46. (a) Smellie, A.; Teig, S. L.; Towbin, P. Poling: Promoting Conformational Coverage. J. Comput. Chem. 1995, 16, 171-187.
47. (b) Smellie, A.; Kahn, S. D.; Teig, S. L. An Analysis of Conformational Coverage. 1. Validation and Estimation of Coverage. J. Chem. Inf. Comput. Sci. 1995, 35, 285-294.
48. Smellie, A.; Kahn, S. D.; Teig, S. L. An Analysis of Conformational Coverage. 2. Applications of Conformational Models. J. Chem. Inf. Comput. Sci. 1995, 35, 295-304.
49. Gillet, V. J.; Khatib, W.; Willet, P.; Fleming, P. J.; Green, D. V. S. Combinatorial Library Design Using a Multiobjective Genetic Algorithm. J. Chem. Inf. Comput. Sci. 2002, 42, 375-385.
50. Rogers, D.; Hopfinger, A. J. Application of Genetic Function Approximation to Quantitative Structure - Activity Relationships and Quantitative Structure - Property Relationships. J. Chem. Inf. Comput. Sci. 1994, 34, 854-866.
51. Shadow descriptors are calculated by projecting the molecular surface on three mutually perpendicular planes, XY, YZ, and XZ, as described in Rohrbaugh, R. H.; Jurs, P. C. Descriptions of Molecular Shape Applied in Studies of Structure/Activity and Structure/Property Relationships. Anal. Chim. Acta 1987, 199, 99-109.
52. Stanton, D. T. On the Physical Interpretation of QSAR Models. J. Chem. Inf. Comput. Sci. 2003, 43, 1423-1433.
53. (a) Kier, L. B.; Hall, L. H. Molecular Connectivity in Structure - Activity Analysis; John Wiley & Sons: New York, 1986.
54. (b) Kier, L. B.; Hall, L. H. Molecular Connectivity. VII. Specific Treatment of Heteroatoms. J. Pharm. Sci. 1976, 65, 1806-1809.
55. Higher CHI values are associated with an increased molecular complexity in terms of both alkyl chain length and substitution pattern. On this basis, such a variable (with a positive sign in the QSAR equation) is able to account for the general trend found for affinity values that are very high for alkyl spacers shorter than an ethyl moiety and decrease for polymethylene chains up to eight carbon atoms.
56. GOLPE 4.5.12; Multivariate Analyses: Perugia, Italy, 1999.
57. GRID 21; Molecular Discovery Ltd: Pinner, Middlesex, U. K.
58. 1-Adrenergic Receptor Antagonists. Bioorg. Med. Chem. 1999, 7, 2437-2451.
59. 1-Adrenoceptor Ligands. J. Med. Chem. 2005, 48, 2420-2431.
60. AC descriptors simply report the number of that atom type in a molecule. In particular, AC2 is referred to the number of CH2R2 carbon atom types (where R indicates any group linked through carbon), which is in turn related to the length of the alkyl spacer. AC9, counting the number of carbon atoms belonging to the CHRX2 type (where X represents any heteroatom), is always associated with the presence of the benzodioxane moiety in our set of molecules, whereas AC27 (carbon atom belonging to aromatic heterocycle) is present only in imidazolyl-pyridazinone and pyridinyl-piperazine compounds. SssCH2 is an electrotopological descriptor related to the carbon atom belonging to a methylene unit involved into two single bonds. It is mainly correlated to the alkyl chain acting as a spacer but also to eventual alkyl chains, such as substituents of the arylpiperazinyl moiety. Finally, SC3C (Subgraph Count Index) encodes for a particular cluster of three heavy atoms, thus related to molecule connectivity.