Kappai Receptors

Kappa receptors were first proposed from detailed pharmacological studies using a series of opiates long before the identification of its endogenous ligand, dynorphin A. Like the delta receptor, efforts to define kappa receptor pharmacology have been difficult due to the stability and selectivity of dynorphin A. The synthesis of highly selective ligands has helped to define the kappa1 receptor, both biochemically and pharmacologically. Kappa1 receptors can produce analgesia, but they do so through mechanisms different from those of the other receptor classes. However, kappa receptor ligands have also been associated with

Figure 4 The murine MOR-1 gene has been extensively studied. Ten different exons, the DNA sequences that end up in mRNA, are spliced together in different patterns to make seven different mu receptor variants. Although the human gene has not been explored as completely, there is little reason to believe that it differs significantly.

Figure 4 The murine MOR-1 gene has been extensively studied. Ten different exons, the DNA sequences that end up in mRNA, are spliced together in different patterns to make seven different mu receptor variants. Although the human gene has not been explored as completely, there is little reason to believe that it differs significantly.

a variety of psychomimetic effects, making their clinical utility somewhat limited.

A kappa receptor with the appropriate pharmacological profile has been cloned, KOR-1. It has high homology with the other receptors and is localized within the brain. However, kappai receptors also appear to be present in a variety of immune cells, as demonstrated by binding and molecular biological approaches.

Functionally, the ORL-1 receptor has some unusual actions. Depending on the dose and the site of administration, OFQ/N can be a potent antiopioid peptide, functionally reversing the actions of morphine and other opioid analgesics. However, at higher doses the peptide is analgesic. Antisense mapping studies have suggested that the kappa3 receptor is related to the ORL-1 receptor, but they are not identical. Thus, the pharmacology of OFQ/N and its receptor is quite complex and many issues remain to be evaluated.

D. The Opioid Receptor-like Receptor

A fourth member of the opiate receptor family has been cloned that is highly selective for OFQ/N. As noted previously, OFQ/N has many similarities to the opioid peptides, but it has very poor affinity for the traditional opioid receptors. Similarly, the opioid peptides do not label the ORL-1 receptor. ORL-1 has an interesting pharmacology. Evidence from both binding and pharmacological studies has suggested multiple subtypes of receptors.

The relationship of ORL-1 to the opiate family is unusual. Although there is high homology at the molecular level, traditional opiates do not bind to this site, and its endogenous ligand, OFQ/N, has poor affinity for all the opiate sites as well. It is interesting, however, that OFQ/N is also a heptadecapeptide.

E. Kappa2 and Kappa3 Receptors

Several other kappa receptor classes have been proposed. U50,488H is a potent and highly selective kappa1 receptor agonist. Binding studies revealed additional kappa receptor binding sites insensitive to U50,488H. The first site was termed kappa2 to distinguish it from the U50,488H-sensitive kappa1 site. The difficulty with defining this site pharmacologically resulted from the lack of highly selective ligands. Recently, it has been suggested that the kappa2 receptor may actually represent a dimer consisting of a kappa1 and a delta receptor. Together, the receptors display binding characteristics quite distinct from either kappa1 or delta receptors alone and may correspond to the kappa2 receptor originally observed in binding studies.

The kappa3 receptor was originally proposed using naloxone benzoylhydrazone (NalBzoH), which is a potent analgesic. Its actions are not reversed by highly selective mu, delta or kappa1 receptor antagonists, giving it a very unique selectivity profile. Recently, its actions have been associated with the ORL-1 receptor. Antisense mapping studies revealed that KOR-3, the cloned mouse homolog of the ORL-1 receptor, and the kappa3 receptor are both encoded by the same gene but are not identical and may be splice variants of the KOR-3/ORL-1 gene. The exact relationship between the kappa3 receptor and the KOR-3/ORL-1 gene has not been completely defined.

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