To characterize the structure-activity relationship between alpha1-adrenergic receptors and the family of imidazoline/guanidinium receptive sites (IGRS), we synthesized and characterized a series of analogues of cirazoline, an imidazoline with high affinity for alpha1-adrenergic receptors and IGRS. Analysis of potency, affinity and efficacy of the synthesized molecules indicate different structure-activity relationships for IGRS and alpha-adrenergic receptors. Cirazoline exhibits a 25-fold higher affinity for IGRS (pKi 7.9) than for alpha1-adrenergic receptors. Replacement of the cyclopropyl ring with an isopropoxy group resulted in a molecule that was 20-fold more selective for alpha1-adrenergic receptors than for IGRS, i.e. a 500-fold increase in selectivity relative to cirazoline. The unsubstituted derivative 3 and the methyl and allyl substituted analogues 4 and 12 are of particular interest: compounds 3 and 4 recognize IGRS with high affinity (pKi 7.83 and 8.17) and high selectivity (398 and 123) with respect to the alpha1-adrenergic receptor; compound 12 also recognizes IGRS with high affinity (pKi 8.08) and high selectivity (228 and 138) with respect to the alpha2B and alpha2c-adrenergic receptor subtypes. Thanks to their IGRS selectivity, these compounds represent novel and valuable pharmacological tools for the characterization and elucidation of the physiological role of these novel sites.

Separation of alpha-adrenergic and imidazoline/guanidinium receptive sites (IGRS) activity in a series of imidazoline analogues of cirazoline

PIGINI, Maria;MARUCCI, Gabriella;QUAGLIA, Wilma;
1995-01-01

Abstract

To characterize the structure-activity relationship between alpha1-adrenergic receptors and the family of imidazoline/guanidinium receptive sites (IGRS), we synthesized and characterized a series of analogues of cirazoline, an imidazoline with high affinity for alpha1-adrenergic receptors and IGRS. Analysis of potency, affinity and efficacy of the synthesized molecules indicate different structure-activity relationships for IGRS and alpha-adrenergic receptors. Cirazoline exhibits a 25-fold higher affinity for IGRS (pKi 7.9) than for alpha1-adrenergic receptors. Replacement of the cyclopropyl ring with an isopropoxy group resulted in a molecule that was 20-fold more selective for alpha1-adrenergic receptors than for IGRS, i.e. a 500-fold increase in selectivity relative to cirazoline. The unsubstituted derivative 3 and the methyl and allyl substituted analogues 4 and 12 are of particular interest: compounds 3 and 4 recognize IGRS with high affinity (pKi 7.83 and 8.17) and high selectivity (398 and 123) with respect to the alpha1-adrenergic receptor; compound 12 also recognizes IGRS with high affinity (pKi 8.08) and high selectivity (228 and 138) with respect to the alpha2B and alpha2c-adrenergic receptor subtypes. Thanks to their IGRS selectivity, these compounds represent novel and valuable pharmacological tools for the characterization and elucidation of the physiological role of these novel sites.
1995
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/242158
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