Irreversible ligands as probes for drug receptors.

Electrophilic and photoactivated agents have proven to be useful as receptor-selective irreversible probes. These compounds are generally derivatives of selected ligands that may be chemically modified in such a way as to retain high receptor affinity and selectivity while permitting covalent bonding to the receptor protein. The receptor systems described in this chapter are associated with a variety of classes of abused drugs. These irreversible agents are allowing the isolation and purification of these drug receptors to improve our understanding of their physiological and pharmacological properties and to aid us in better design of agents with therapeutic value without abuse or physical dependence liability. In the opioid field, beta-FNA and SUPERFIT have been successfully used to elucidate structure and function of the mu-, kappa-, and delta-receptors, respectively. Recently, the delta- and kappa-subtype selective irreversible ligands naltrindol and UPHIT have been introduced for receptor subtype studies that are designed to further clarify the physiological function of these sites. The PCP recognition site on the NMDA receptor complex and the sigma receptors have been characterized in part by the use of irreversible agents. These receptors, although sharing similar pharmacological properties, are clearly different systems and the irreversible agents described will allow their further characterization. The central-type benzodiazepine receptors have been labeled with irreversible agents; and, now, receptor subsites that differentially recognize beta-carbolines and benzodiazepines have been discovered through studies using a beta-carboline photoaffinity probe. The associated chloride ionophore has been studied with electrophilic irreversible ligands, as well as the pharmacologically distinct peripheral-type benzodiazepine receptors. Physiological function of the latter receptor system has been implicated through the photoaffinity ligand PK 14105, which is highly selective for these sites. Receptor subtype selective irreversible ligands also have been prepared for both the dopamine and sertonin receptors systems in hopes of clarifying their physiological roles in the CNS. It is clear that more selective irreversible compounds with higher affinity will continue to be in demand for further receptor characterization. In addition, radioligands with higher specific activity will continue to be important for molecular weight determination of receptor proteins and autoradiographic studies key to neuroanatomical localization of these sites.