α1-adrenoceptor activation: A comparison of 4-(Anilinomethyl)imidazoles and 4-(Phenoxymethyl)imidazoles to related 2-imidazolines

Bioorganic and Medicinal Chemistry Letters

Volumn 12, Issue 23, 2002, Pages 3449-3452

  Hodson, Stephen J ^a   Bigham, Eric C ^a   Garrison, Deanna T ^a   Gobel, Michael J ^a   Irving, Paul E ^a   Liacos, James A ^a   Navas, Iii, Frank ^a   Saussy Jr , David L ^a   Sherman, Bryan W ^a   Speake, Jason D ^a   Bishop, Michael J ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA 1 ADRENERGIC RECEPTOR; ALPHA 1 ADRENERGIC RECEPTOR STIMULATING AGENT; IMIDAZOLE DERIVATIVE; IMIDAZOLINE DERIVATIVE; RECEPTOR SUBTYPE; ALPHA ADRENERGIC RECEPTOR STIMULATING AGENT; ANILINE DERIVATIVE; DIPHENYL ETHER DERIVATIVE; RECOMBINANT PROTEIN;

ARTICLE; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; CHEMISTRY; COMPARATIVE STUDY; DRUG POTENTIATION;

ADRENERGIC ALPHA-AGONISTS; ANILINE COMPOUNDS; HUMANS; IMIDAZOLES; PHENYL ETHERS; RECEPTORS, ADRENERGIC, ALPHA-1; RECOMBINANT PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 18644362076     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00753-9     Document Type: Article

References (30)

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24. For an example of literature precedent, see: Jacobs R. J. Heterocycl. Chem. 7:1970;1337.
25. Sulfone final products were typically produced via oxidation of the sulfides, as previously described: Hodson S.J., Bishop M.J., Speake J.D., Navas F., Garrison D.T., Bigham E.C., Saussy D.L. Jr., Liacos J.A., Irving P.E., Gobel M.J., Sherman B.W. J. Med. Chem. 45:2002;2229.
26. 1D (clone #16-7)-adrenoceptors were expressed in Rat-1 fibroblast cells. Receptor activation was determined via calcium mobilization through the Gq coupled PLC pathway using calcium-sensitive fluorescent dyes (Calcium Green, Molecular Probes C 3011), measured by a Fluorescent Light Imaging Plate Reader (FLIPR). Eleven point concentration-response curves were calculated as percent of the 40 μM phenylephrine response, with the highest sample concentration typically 5 μM. The assay results for NS-49 and cirazoline are shown for comparative purposes.
27. 1A-subtype selectivity observed in the cell-based agonist functional assays did not correlate directly with subtype selectivity in receptor binding assays.
28. Navas F., Bishop M.J., Garrison D.T., Hodson S.J., Speake J.D., Bigham E.C., Drewry D.H., Saussy D.L. Jr., Liacos J.A., Irving P.E., Gobel M.J. Bioorg. Med. Chem. Lett. 12:2002;475. See also ref 4(b).
29. For amides in the 2-(anilinomethyl)imidazoline series, a hydrogen bond between the amide carbonyl and the N-H of the aniline appears to be important for achieving the active conformation with the receptor, and 2-(phenoxymethyl)imidazoline amide compounds such as 19 cannot make this type of hydrogen bond. The same phenomena was observed for amides in the 4-imidazole series, indicated that the potential for hydrogen bonding between the amide carbonyl and the linker N-H may be important in the 4-(anilinomethyl)imidazole series also. See: Bishop M.J., Berman J., Bigham E.C., Garrison D.T., Gobel M.J., Hodson S.J., Irving P.E., Liacos J.A., Minick D.J., Navas F., Saussy D.L. Jr., Speake J.D. Bioorg. Med. Chem. Lett. 11:2001;2871.
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