Affinity of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines for α-adrenoceptors. differential affinity of imidazolines for the [3h]idazoxan-labeled α2-adrenoceptor vs the [3h]yohimbine-labeled site

Journal of Medicinal Chemistry

Volumn 33, Issue 2, 1990, Pages 596-600

  Clark, Robin D ^a   Berger, Jacob ^a   Garg, Pushkal ^a   Weinhardt, Klaus K ^a   Kilpatrick, Andrew T ^b   Brown, Christine M ^b   MacKinnon, Alison C ^b  

^a ROCHE BIOSCIENCE   (United States)

^b Syntex Research   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 (1,2,3,4 TETRAHYDRO 2 ISOQUINOLYLMETHYL) 2 IMIDAZOLINE DERIVATIVE; 2 [(8 CHLORO 1,2,3,4 TETRAHYDRO 2 ISOQUINOLYL)METHYL] 2 IMIDAZOLINE; 2 ISOINDOLINYLMETHYL 2 IMIDAZOLINE DERIVATIVE; ALPHA 2 ADRENERGIC RECEPTOR; IDAZOXAN; RADIOISOTOPE; RAUWOLSCINE; UNCLASSIFIED DRUG; YOHIMBINE;

ANIMAL CELL; ARTICLE; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SYNTHESIS; INFRARED SPECTROPHOTOMETRY; MASS SPECTROMETRY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; PRIORITY JOURNAL; RAT;

ANIMAL; BINDING SITES; BINDING, COMPETITIVE; CEREBRAL CORTEX; CHEMISTRY, PHYSICAL; DIOXANES; IDAZOXAN; IMIDAZOLES; IN VITRO; INDOLES; ISOQUINOLINES; LIGANDS; PRAZOSIN; RADIOLIGAND ASSAY; RATS; RECEPTORS, ADRENERGIC, ALPHA; STRUCTURE-ACTIVITY RELATIONSHIP; YOHIMBINE;

EID: 0025159310     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm00164a021     Document Type: Article

References (36)

1. Contribution No. 762 from the Institute of Organic Chemistry.
2. Clark, R. D.; Michel, A. D.; Whiting, R. L. Prog. Med. Chem. 1986, 23, 2.
3. Pinder, R. M. Drugs Future 1985,10, 841.
4. Chapleo, C. B.; Myers, P. L.; Butler, R. C. M.; Doxey, J. C.; Roach, A. G.; Smith, C. F. C. J. Med. Chem. 1983, 26, 823.
5. Armah, I. B.; Ferry, D. R.; Glossmann, H. Br. J. Pharmacol. 1983, 78 (Suppl.), 151P.
6. Wentland, M. P.; Bailey, D. M.; Alexander, E. J.; Castaldi, M. J.; Ferrari, R. A.; Haubrich, D. R.; Luttinger, D. A.; Perrone, M. H. J. Med. Chem. 1987, 30, 1482.
7. Hlasta, D. J.; Luttinger, D.; Perrone, M. H.; Silbernagel, M. J.; Ward, S. J.; Haubrich, D. R. J. Med. Chem. 1987, 30,1555.
8. Fagan, G. P.; Chapleo, C. B.; Lane, A. C.; Myers, M.; Roach, A. G.; Smith, C. F. C.; Stillings, M. R.; Welbourn, A. P. J. Med. Chem. 1988, 31, 944
9. Compounds of formula 6 have independently been the subject of several patent applications: GB Appl. 85-29, 546,1985. Also see: Chem. Abstr. 1987, 107, 1760377.
10. Anilkumar, P. P.; Bauer, L. J. Heterocycl. Chem. 1966, 3, 472.
11. Seebach, D.; Yoshifuji, M. Helu. Chim. Acta 1981, 64, 643.
12. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1984, 32, 2421.
13. Bondinell, W. E.; Chapin, F. W.; Girard, G. R.; Kaiser, C.; Krog, A. J.; Pavloff, A. M.; Lam, B. L.; Wellman, G. R.; Pen-delton, R. G. J. Med. Chem. 1980, 23, 506.
14. Durand, S.; Lusinchi, X.; Moreau, R. C. Bull. Chim. Soc. Fr. 1961, 270.
15. Goldstein, M.; Saito, M.; Lew, J. Y.; Hieble, J. P.; Pendelton, R. G. Eur. J. Pharmacol. 1980, 67, 305.
16. 5,6-Dimethoxy-3,4-dihydroisoquinoline: Haworth, R. D. J. Chem. Soc. 1927, 2281.
17. Aldrich Chemical Co.
18. Mata, R.; Chang, C. J.; McLaughlin, J. L. Phytochem. 1983,22, 1263.
19. Rao, K. V.; Jackman, D. J. Heterocycl. Chem. 1973,10, 213.
20. The dihydroisoquinoline is known: Sugasawa, S.; Shigehara, H. Chem. Ber. 1941, 74, 459
21. Whaley, W. M.; Grovindachari, T. R. Org. React. 1951, 6, 74.
22. Mendelson, W. L.; Spainhour, C. B.; Jones, S. S.; Lam, B. L.; Wert, K. L. Tetrahedron Lett. 1980, 21, 1393.
23. Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572.
24. Dubois, R. J.; Lin, C. L.; Beisler, J. A. J. Med. Chem. 1978,21, 303.
25. Compound 8b was subsequently found to be a partial α1-agonist in functional assays (contraction of rabbit aortic strip) and to elevate blood pressure directly in pithed rats. Partial α1-agonist activity has been reported for idazoxan (1) and BDF-6143 (2), ref 2 and citations therein, and for compound 4, ref 7b.
26. Compound 5m was also found to be a partial α2-adrenoceptor agonist in the guinea pig ileum, but only at high concentrations (1 µM, 50% inhibition of electrically evoked contractions at 9 µM).
27. The observed pKi differences did not appear to result from the different buffers used in the α2-adrenoceptor binding assays (Tris HCl, pH 7.4 for [3Hiyohimbine binding; physiological salt solution, pH 7.4, for [3Hidazoxan binding). For example, in the [3Hidazoxan binding assay using physiological buffer, pKi values of 7.25 ± 0.07 and 8.12 ± 0.05 were determined for the standards yohimbine and idazoxan, respectively, compared with values of 7.36 ± 0.10 and 8.09 ± 0.10, respectively, in the Tris HCl buffer. In the same assay, 5m had pKi values of 8.23 ± 0.08 in the physiological buffer and 8.55 ± 0.15 in the Tris HCl buffer.
28. Stillings, M. R.; Chapleo, C. B.; Butler, R. C.; Davis, J. A.; England, C. D.; Myers, M.; Myers, P. L. Tweddle, N.; Welboum, A. P.; Doxey, J. C.; Smith, C. F. C. J. Med. Chem. 1985, 28, 1054.
29. Vici, E. S. Med. Res. Rev. 1986, 6, 431.
30. Bylund, D. B. Pharmacol. Biochem. Behav. 1985, 22, 835.
31. Nahorski, S. R.; Barnett, D. B.; Cheung, Y. D. Clin. Sci. 1985, 10, 39s–42s.
32. Boyajian, C. L.; Loughlin, S. E.; Leslie, F. M. J. Pharmacol. Exp. Ther. 1987, 241, 1079.
33. Boyajian, C. L.; Leslie, F. M. J. Pharmacol. Exp. Ther. 1987, 241, 1092.
34. Newman, M. S.; Scheurer, P. G. J. Am. Chem. Soc. 1956, 78, 5004.
35. Noyes, W. A.; Porter, P. K. Organic Syntheses; Wiley: New York, 1941; Collect. Vol. I, 457.
36. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099.