Receptor binding, irreversible

Yet, cyclazocine was able to displace the binding of 3H-PCP. These findings are consistent with the finding that metaphit can only bind irreversibly to about 50 percent of the receptors labeled by 3H-PCP (Rafferty et al. 1985), which indicates that 3H-PCP binds to more than one type of receptor. Thus, PCP and cyclazocine probably exert their effects through different receptors. 

Attaching an isothiocyanate group to the aromatic ring of U-50488 has been reported to produce the first site-directed alkylating agent to bind irreversibly to kappa receptors in guinea-pig membranes [51]. 

Phenoxybenzamine binds covalently to receptors, causing irreversible blockade of long duration (14-48 hours or longer). It is somewhat selective for Ki receptors but less so than prazosin (Table 10-1). The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (Hi), acetylcholine, and serotonin receptors as well as receptors (see Chapter 16). 

When an antagonist binds irreversibly to the receptor site, thus producing either permanent chemical changes or inactivation of the receptor site, or both, this is referred to as noncompetitive... 

Rothman RB, Long JB, Bykov V, Jacobson AE, Rice KC, Holaday JW. Beta-FNA binds irreversibly to the opiate receptor complex in vivo and in vitro evidence. J Pharmacol Exp Ther 1988 247 405 416. 

The reason for the irreversible opioid agonist and antagonist actions of 14-hydroxydihydromorphinone hydrazones (170, 171, and 172) has been attributed 261 to the formation of their respective azines (173). These azines, which may form if a large excess of hydrazine is not used during the synthesis of the hydrazones, have been found to be stable and to block opioid receptor binding in vitro irreversibly at 20-40 times the potency of their corresponding hydrazones. 

Covalent bonds are not as important in drug-receptor binding as noncovalent interactions. Alkylating agents in chemotherapy tend to react and form an immonium ion, which then alkylates proteins, preventing their normal participation in cell divisions. Baker s concept of active site directed irreversible inhibitors was well established by covalent formation of Baker s antifolate and dihydrofolate reductase (46). 

Drugs that bind irreversibly to receptors include phenoxybenzamine (to the a-adrenoceptor). Since such a drug cannot be displaced from the receptor, increasing the concentration of agonist does not fully restore the response and antagonism of this type is said to be insurmountable. 

Marjamaki A, Pihlavisto M, Cockcroft V, Heinonen P, Savola JM, Scheinin M. Chloroethylclonidine binds irreversibly to exposed cysteines in the fifth membrane-spanning domain of the human a2A-adrenergic receptor. Mol Pharmacol 1998 53 370-376. 

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