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Jeffrey S. Gaynes, Jeffrey A. Borgia, Bruce I. Gaynes; Melanin Binding Characteristics Of α-1 Adrenergic Receptor Antagonists. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5673.
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To elucidate binding characteristics of α-1 antagonists with and without a sulfonyl moiety to synthetically prepared melanin.
Alpha 1 antagonists selected for study included tamsulosin HCL and prazosin HCL. The chemical structure of tamsulosin is notable for a substituted sulfonyl group. Synthetic melanin was created via enzymatic action between L-DOPA and polyphenol oxidase. The formed melanin was centrifuged at 15,000 x g for 20 minutes at 4o centigrade and washed five times by resuspending in distilled water, followed by recentrifugation. Freeze drying of the pellet yielded between 140-160 mg of melanin. Solutions of tamsulosin and prazosin were created at 10-3mg/mL concentrations respectively. Concentration gradients of each drug were then created at 10-3, 0-4, and 10-5 mg/mL respectively to form a standard curve. Synthesized melanin was then incubated and agitated overnight with each drug sample. Following incubation each sample was washed with phosphate buffer three times. The washed sample was mixed with acetonitrile and centrifuged; the melanin was then discarded and the eluent collected and analyzed via tandem mass spectrometry to determine bound concentration.
Mass spectroscopic analysis of the final concentration of tamsulosin and prazosin bound to melanin was found to be 3.6µg/mL and 0.3µg/mL respectively.
Tamsulosin HCL bound to synthetic melanin in a manner twelve times greater than prazosin. Tamsulosin posses a notable sulfonyl group in its chemical structure, which may alter charge dispersal forces of the molecule to enhance melanin binding affinity. Interestingly, molecular comparisons of tamsulosin and chloroquine, a common anti-malarial drug with a notable melanin binding affinity demonstrate remarkable similarities in that that both compounds display secondary amine and sulfonyl amino groups with similar pKa values. One may predict that, similar to chloroquine, tamsulosin exists in the doubly protonated highly cationic form at physiologic pH, qualities that define binding affinity for melanin. It is possible that tamsulosin’s melanin binding action may foster an explanation for tamsulosin induced intraoperative floppy iris syndrome (IFIS).
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