Delta-opioid agonist

Sofuoglu M, Portoghese P, Takemori A. Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice evidence for delta opioid receptor subtypes. 

Noble, F., Smadja, C., Roques, B.P Role of endogenous cholecystokinin in the facilitation of mu-mediated antinociception by delta-opioid agonists, J. Pharmacol. Exp. Ther. 1994, 271, 1127-1134. 

Dondio, G., Clarke, G.D., Giardina, G., et al. The role of the spacer in the octahydroisoquinoline series discovery of SB 213698, a non-peptidic, potent and selective delta opioid agonist, Analgesia 1995, 1, 394-399. 

Dondio, G., Ronzoni, S., Petrillo, P. Non-peptide delta opioid agonists and antagonists (Part II), Exp. Opin. Ther. Patents 1999, 9, 353-374. 

Nagase, H., Wakita, H., Kawai, K. Synthesis of non-peptidic delta opioid agonists and their structure activity relationships, Jpn. J. Pharmacol. 1994, 64, 35. 

Scheideler, M.A. Evidence for the role of delta opioid agonists in pain signaling, Curr. Opin. CPNS Invest. Drugs 2000, 2, 171-177. 

Kondo I, Marvizon JC, Song B, et al. Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release. J Neurosci. 2005 25 3651-3660. 

The discovery of BW373U86 from this early effort enabled a significant amount of pharmacological investigation into the effects of a selective delta opioid agonist. Studies on BW373U86, which is a potent, selective, delta... 

Another successful approach to replacing the benzhydryl stereocenter has been to synthesize and evaluate diarylamines with pendant basic amines. A simple transposition of the nitrogen and carbon atoms of the benzhydryl-piperazine leads to diarylaminopiperidine delta opioid agonists, as Carroll and coworkers at the Research Triangle Institute (RTI) demonstrated [30]. Scientists at AstraZeneca [31] and the R.W. Johnson Research Institute [32] have also disclosed delta opioid agonists possessing the carbon-nitrogen transposition. Boyd and coworkers at R.W. Johnson were the first to report on compounds where the aminopiperidine was further constrained as an aminotropane. Compound 47 has a K = 0.4 nM at the delta opioid receptor, with 14000-fold selectivity versus the mu opioid receptor (Fig. 8). 

MIXED MU/DELTA OPIOID AGONISTS IN THE BENZHYDRYLPIPERAZINE SERIES... 

CELLULAR EFFECTS OF INVERSE DELTA OPIOID AGONISTS... 

Although it has been proven that a number of delta-selective inverse opioid ligands behave as inverse agonists in constitutively active recombinant cell lines, the physiological and therapeutic relevance of the inverse delta opioid agonists is still not completely understood. 

Biochemical studies have shown in vitro and in vivo differential inhib-itory/stimulatory modulation of spinal and supraspinal CCK release by mu and delta opioid agonists. Thus, delta opioid agonists enhance the release of CCK, whereas stimulation of mu opioid receptors reduces its release [81,82], Moreover, it has been shown that activation of CCKi receptors potentiates the analgesic responses induced by mu opioid agonists or by endogenous enkephalins, protected from their catabolism by the dual inhibitor RB 101, while activation of CCK2 receptors reduces them [80]. 

In addition to locomotor activity, delta opioid agonists produce convulsions in mice [41,43], rats [34,35], and monkeys [44 46], In the past, chemical-induced convulsions induced by camphor or pentylenetetrazol (Metrazol) were used as treatments for depression today, however, ECT is the only convulsant therapy used because the treatment-induced effects are less unpleasant than those produced by chemical convulsants [47]. ECS was demonstrated to have antidepressant-like effects in the forced swim test in rats [3], and ECT is a very effective treatment for depression in humans. Based on these observations, it was proposed that delta opioid agonists produce antidepressant-like effects tough a convulsive- or electroconvulsive shock (ECS)-like mechanism of action [41]. 

Although these experiments analyzed the hypothesis that convulsant activity is required for the antidepressant-like effects of ( + )BW373U86, it did not thoroughly address the question of whether seizure activity is required for the antidepressant-like effects of delta opioid agonists. The benzodiazepine midazolam was demonstrated to inhibit seizure activity [49,50] however, seizure activity was not directly measured in the study by Broom et al. [35]. Interestingly, limited work has been done with the seizure activity of delta opioid agonists. One study demonstrated that the delta opioid agonist... 

BW373U86 increased hippocampal type 2 theta power in rat EEG measurements however, this study did not test doses of BW373U86 that would produce convulsions in rats [51]. Therefore, it is difficult to determine the role of seizures in the antidepressant-like effects of delta opioid agonists. This concept must be studied in the future to determine the role of seizure activity or electroencephalographic activity in the antidepressant-like effects of delta opioid agonists. 

Experiments and data presented in this chapter demonstrate that delta opioid agonists have antidepressant-like effects in animal models used to measure antidepressant activity. The antidepressant-like effects can be separated from other behavioral effects produced by these compounds, such as locomotor stimulation, convulsions, and learning impairments. This separation lends validity to this potential target for depression by eliminating effects or sources that may produce false positives. These compounds should be tested in other models of antidepressant activity to confirm these findings in the forced swim test. 

To further develop delta opioid receptor agonists as potential therapeutics, more compounds should be developed and evaluated in the forced swim test and other models of antidepressant activity. This may allow for the identification of delta opioid agonists with even more selective behavioral effects. Indeed, there are a number of delta opioid agonists with different basic chemical structures that may prove useful. 

In conclusion, these data may provide information about the possibility of developing classes of delta opioid agonists that demonstrate potential therapeutic effects of delta opioid agonists, but do not demonstrate convulsions and locomotor-stimulating effects. 

Jutkiewicz EM, Eller E, Rice KC, Woods JH, Behavioral effects in rats of a delta opioid agonist (SNC80) depend upon intravenous infusion rate. XIVth World Congress of Pharmacology. San Francisco, CA, USA, 2002. 

Novel opioid compounds have been synthesized that have analgesic capacity, but lack immunosuppressive effects or even potentiates immune function [60,123-126]. In this respect, Nowak et al. [123] recently reported that the delta opioid agonist SNC 80 did not alter NK cell, lymphocyte, and macrophage functions following ICV administration [123]. Furthermore, IV administration of SNC 80 was associated with ex vivo immunopotentiation, following an activating challenge. 

Reinforcing Effects of Delta Opioid Agonists in Drug Self-Administration Studies... 

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