Opioid peptide-receptor interactions

Ni Q., Xu H., Partilla J. et al. Opioid peptide receptor studies. Interaction of opioid peptides and other drugs with four subtypes of the K2 receptor in guinea pig brain. Peptides. 16 1083, 1995. 

A novel endogenous opioid peptide with significant sequence homology to dynorphin A was alternatively termed nociceptin or orphanin FQ (now termed N/OFQ Table 21-1). The substitution of Phe for Tyr in the opioid motif is sufficient to abolish interactions with the three classical opioid peptide receptors. N/OFQ has behavioral and pain modulatory properties distinct from those of the three classical opioid peptides. 

The third prohormone from which opioid peptides are derived is pro-opiomelanocortin, which yields a number of nonopioid and opioid peptide products (O Donohue and Dorsa 1982). Of these products, beta-endorphin, an untriakontapeptide isolated from camel pituitary gland by Li and Chung (1976)) is thought to interact primarily with mu and delta receptors. 

Simantov, R. Childers, D. and Snyder, S. The opiate receptor binding interactions of 3Hmethionine enkephalin, an opioid peptide. Fur J. Pharmacol 47 319-331, 1978. 

The efficacy and strength of opioid antagonists varies depending on the type of opioid receptors (u-, 8-, K-, a-) with which they interact. The mechanism of their action is not fully clear. However, it has been suggested that they antagonize the action of endogenous opioid peptides. 

Strong evidence indicates at least a familial pattern and perhaps a hereditary basis for some types of alcoholism ( 393). More recent data show that genotype accounts for approximately 33% of the overall variance in liability ( 394). In addition, specific neurocircuitry and neurochemical systems appear to be important in the etiology of alcoholism (395). Thus, positive reinforcement may be mediated by activation of g-aminobutyric acid (GABA) receptors, release of opioid peptides and dopamine, inhibition of glutamate receptors, and interactions with the 5-HT system. Furthermore, neurobehavioral effects of alcohol and their association with these various neurotransmitters serve as potential targets for novel drug therapies. 

The opioids produce their pharmacological effects by interacting with a closely related group of peptide receptors, thereby suggesting that endogenous opioid-like polypeptides exist, which presumably have a physiological function. 

Fig. 8. Known and potential interactions of the ACTH/adenylate cyclase/cyclic AMP-dependent protein kinase system in the adrenocortical cell with other hormones and intracellular messengers. Epinephrine activates adenylate cyclase in the adrenocortical cell [33]. Adrenocortical cells have receptors for several hormones which may activate G, including angiotensin II [34], acetylcholine [35], and endogenous opioid peptides [36]. Angiotensin II, acetylcholine and vasopressin [37-39] have all been demonstrated to activate the breakdown of PIP2 in adrenocortical cells and to stimulate steroidogenesis 5-hydroxytrypt-amine is also a known steroidogenic agent [40]. Probable receptor subtypes involved are indicated (/3 M (muscarinic) 5-HT, and V,). This is not a comprehensive diagramming of all stimuli or all possible interactions. Modified from Ref. 7.

Subsequently, numerous peptides with opioid-like effects have been found in the central nervous system and in peripheral tissues. These endogenous opioid peptides vary in size, but their amino terminals mostly share a similar enkephalin sequence of amino acids. Currently, four separate, individually gene-derived families of endogenous opioid peptides are recognized the endorphins, the enkephalins, the dynorphins and the endomorphins [17a], -Endorphin interacts predominantly with n and 6 receptors, Leu-enkephalin and Met-enkephalin interact predominantly with 5 receptors, dynorphin shows preference for k receptors [17b], while endomorphins 1 and 2 exhibit... 

A series of cyclic conformationally constrained peptides related to somatostatin were designed, synthesized and tested for opioid receptor interaction by Hruby and his collaborators. Compounds (17)-(22) were found to be pure opioid antagonists (GPI) with high affinity (IC50 = 1.2 to 4.3 nM) and exceptional selectivity for p over S opioid receptors (Table 3.1) and with minimal or no somatostatin-like activity (ligand binding assays)[63-65]. 

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