Opioid ‘agonist

Currently, there are no 8 opioid pharmaceuticals on the market moreover, the essential properties of this class of drugs remain unclear. It is unknown whether 8 opioid agonists incur the side effects observed with other opioid drugs, like dependency and constipation. 

SNC-80 (GSK, NIH) [15] is one of the leading 8 opioid agonists in development. SNC-80 has a bisarylmethyl substituted piperazine substructure (Fig. 2). Some SNC-80 derivatives for treating pain or urinary incontinence are in clinical development, including DPI-3290 [16] (8 and p opioid agonist GSK, Enhance Biotech), PF-04856880 [17] (ADL-5859 Pfizer, Adolor), PF-04856881 [18] (ADL-5747 Pfizer, Adolor), and a dimethylpiperazine derivative [19] (University of Arizona, NIH) (Fig. 2). 

1 Shionogi reports Financial Results for the Third Quarter of Fiscal Year 2009, Shionogi Press Release 2010, February 1. 

Our group is currently developing TAN-67 (Toray), another lead opioid agonist with a characteristic 4a-aryl-decahydroisoquinoline structure. We previously discussed the design rationale and pharmacology of this compound [20, 21]. 

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Fig. 1. Structures of two types of opioid agonists where dotted circles surround structural elements common to both compounds (a) Leu-enkephalin and...

Fig. 4. Structures of several nonpeptide opioid agonists, (a) morphine, (c) BW373U86, (e) U50488 and antagonists, (b) naloxone, (d) naltrindole, and (f)...

Table 3. Drugs Exhibiting Both Opioid Agonist and Antagonist Activities...

Central and peripheral analgesic agents from kappa-opioid agonists 95E405. 

Opiate overdose is a medical emergency that can result in respiratory and CNS depression. The opioid receptor antagonist naloxone immediately reverses cardiorespiratory depression. However, repeated naloxone administration is required, since the effects of naloxone last for 30 min, while opioid agonists can remain at potentially lethal blood levels for several hours. 

The abrupt cessation of a repeatedly or continuously administered opioid agonist, or the administration of an antagonist typically results in the withdrawal syndrome. Signs and symptoms include sweating, tachycardia, hypertension, diarrhea, hyperventilation, and hyperre-flexia. 

Kang J, Chen XL, Wang H, et al Interactions of the narcotic 1-alpha-acetylmethadol with human cardiac K+ channels. Eur J Pharmacol 458 25-29, 2003 Katchman AN, McGroary KA, Kilborn MJ, et al Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther 303 688-694, 2002... 

Patel MB, Patel CN, Rajashekara V, et al Opioid agonists differentially regulate U-opioid receptors and trafficking proteins in vivo. Mol Pharmacol 62 1464-1470, 2002... 

In further support of a pro-nociceptive role of CX3CL1 are data showing that the direct injection of CX3CL1 in the periaqueductal grey, a brain region mostly involved with analgesic responses, albeit un-effective by itself, results in inhibition of the antinociceptive effects induced by p, 5, and k opioid agonists (Chen et al. 2(X)7). 

Bohn LM, Belcheva MM, Coscia CJ (2000) p-opioid agonist inhibition of kappa-opioid receptor-stimulated extracellular signal-regulated kinase phosphorylation is dynamin-dependent in C6 glioma cells. J Neurochem 74 574-581... 

Regulation of Neuronal Chemokine Receptor CXCR4 by X-Opioid Agonists and Its Involvement in NeuroAIDS... 

Regulation of Neuronal Chemoldne Receptor CXCR4 by p-Opioid Agonists... 

Chen X, Geller EB, Rogers TJ, Adler MW (2007) The chemokine CX3CLl/fractaUdne interferes with the antinociceptive effect induced by opioid agonists in the periaqueductal grey of rats. Brain Res 1153 52-57... 

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