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Iodocyanopindolol
Drug From Wikipedia, the free encyclopedia
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Iodocyanopindolol (INN), also known as ICYP, is a synthetic compound derived from pindolol, primarily used as a radioligand in pharmacological research. It functions as a non-selective β-adrenoceptor antagonist and a serotonin 5-HT1A and 5-HT1B receptor antagonist.[1] Its 125I-radiolabelled derivative, [125I]-iodocyanopindolol ([125I]-ICYP), is widely employed to map the distribution and density of β-adrenoceptors and serotonin receptors in tissues, particularly in the brain, heart, and other organs.[2] Iodocyanopindolol is not used clinically but remains a critical tool in studying receptor pharmacology and signal transduction.[3] Its application extends to the central nervous system, where it labels 5-HT1B receptors in regions like the brainstem, hippocampus, and cortex, aiding research on serotonin autoreceptor regulation.[4]
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Pharmacological properties
Iodocyanopindolol acts as a high-affinity antagonist at β1 and β2 adrenoceptors, with a lesser affinity for β3 adrenoceptors. It also antagonizes 5-HT1A and 5-HT1B serotonin receptors, making it a versatile radioligand for studying both adrenergic and serotonergic systems.[1] The [125I]-ICYP form binds with high specificity, allowing quantitative analysis of receptor density (Bmax) and affinity (Kd) through techniques like autoradiography and radioligand binding assays.[5]
The binding of [125I]-ICYP to β-adrenoceptors is modulated by G-protein coupling. For example, guanine nucleotides like GTP reduce its affinity for 5-HT1B receptors by disrupting receptor-G-protein interactions, as observed in rat brain studies. This property enables researchers to distinguish high-affinity (G-protein-coupled) and low-affinity receptor states.[6]
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Research applications
[125I]-Iodocyanopindolol is extensively used to map β-adrenoceptor distribution in tissues such as the human heart, rat lung, and urinary bladder. Early studies demonstrated its utility in identifying coexisting β1- and β2-adrenoceptors in the human right atrium, providing insights into cardiac receptor pharmacology.[3] Its application extends to the central nervous system, where it labels 5-HT1B receptors in regions like the brainstem, hippocampus, and cortex, aiding research on serotonin autoreceptor regulation.[4]
In competition binding experiments, [125I]-ICYP has been used to assess the selectivity of β-adrenergic antagonists. For instance, studies in rat brain showed that β1-selective antagonists (e.g., atenolol, metoprolol) and β2-selective antagonists (e.g., ICI-118,551) exhibit distinct displacement profiles, confirming receptor subtype specificity.[7] Recent research has explored its potential to label β3-adrenoceptors in rat urinary bladder, though challenges with non-specific binding limit its reliability for this subtype.[8]
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Mechanism and binding characteristics
The radiolabelled [125I]-ICYP binds with high affinity to β-adrenoceptors (Kd ≈ 0.037–0.056 nM in rat brain) and 5-HT1B receptors, modulated by assay conditions like magnesium ions or guanine nucleotides. For example, 5 mM MgSO4 increases [125I]-ICYP affinity for 5-HT1B sites, while GTP or Gpp(NH)p reduces it, reflecting G-protein-mediated effects.[6] In competition assays, agonists like isoproterenol displace [125I]-ICYP with lower potency in the presence of GTP, indicating a shift from high- to low-affinity receptor states.[9]
Non-specific binding remains a challenge, particularly in tissues with low receptor density or when studying β3-adrenoceptors. Studies suggest that compounds like SR 59,230A may compete for non-specific [125I]-ICYP sites, complicating data interpretation.[8] Researchers often use selective antagonists or alternative radioligands (e.g., [3H]-CGP12177) to validate findings.[7]
History
Iodocyanopindolol was first characterized in the early 1980s as a radioligand for β-adrenoceptors, with its 125I derivative introduced by Brodde et al. for cardiac receptor studies.[3] Its dual affinity for β-adrenoceptors and 5-HT1B receptors was later exploited in neuroscience, particularly in the 1990s, to investigate serotonin receptor regulation in rat models.[4] The compound’s development built on pindolol’s established pharmacology, enhancing its utility through radiolabeling for precise receptor mapping.[2]
Despite its research prominence, iodocyanopindolol has not been developed for clinical use due to its lack of therapeutic specificity and the availability of more targeted β-blockers like atenolol or metoprolol. Its radiolabelled form remains a niche tool, valued for its high sensitivity in experimental settings.[5]
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See also
References
External links
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