Opioid agonists and antagonists

Heybroek et used PGEs (Ei +0.4 V, E2 +0.9 V vs Pd) in the analysis of codeine and morphine in plasma and gastric juice. Sample preparation was by on-line extraction (ethyl-modified silica column). Codeine-6-glucuronide was measured as codeine after off-line enzymic hydrolysis. Svensson et measured morphine, normorphine and M-6-G as metabolites of codeine using PGEs (Ei +0.25 V, E2 +0.35 V vs Pd) but, because of the low potentials used, the 3-methyl 

Nalmefene has been measured in plasma using a phenyl-modified silica analytical column with acetonitrile-water (30 -f- 70) containing sodium pentane-sulfonate (5mmolL ) and orthophosphoric acid (0.0045% v/v) (final pH 3.1) as eluent, and ED (PGEs, Ei -1-0.23 V, E2 -1-0.35 V V5 Pd). Sample preparation was via SPE (cyanopropyl-modified silica column) and nalbuphine was the internal standard. The LoD was 1 pg L (0.7 mL sample). 

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

Fig. 37.4. Spectral map of the 26 opioid agonists and antagonists in 4 receptor binding tests, as described by Table 37.7 [45, 46]. Circles refer to the compounds. Squares represent the binding tests. Areas of circles and squares are proportional to the marginal mean affinities in the table. The lines that join the three poles (DHM, DADLE and EKC) of the map represent axes of contrast between the p-, 8-and K-opioid receptors. The horizontal and vertical components represent 18 and 79%, respectively, of the interaction in the data.

The primary purpose of this chapter is to review the structure-activity relationships (SAR) of non-peptide kappa opioid agonists and antagonists from the viewpoint of a medicinal chemist. It is intended to present an account of work in this area published in journals and in patents from 1985 up to the end of 1990. During the late 1980 s there was a significant increase in the literature on kappa opioids and this has resulted in several publications which, at the time of writing, have not been previously reviewed. Three pharmaceutical companies, Upjohn, Parke-Davis and Zambeletti (SB-Italy), have progressed kappa agonists into clinical trials, so it seems an appropriate and opportune time to review the preclinical data. 

The biochemical and pharmacological properties of the kappa receptor and the differences between the kappa, mu and delta receptors have been reviewed elsewhere. The reader is directed to the opioid review articles by Rees and Hunter (1990) [4], Casy (1989) [3] and Leslie (1987) [10] and also to two shorter reviews which deal specifically with kappa agonists the review by Horwell published in 1988 entitled Kappa Opioid Analgesics [8] and the review by Millan in 1990 on kappa opioid receptors and analgesia [9]. An account of the medicinal chemistry of selective opioid agonists and antagonists was published in 1990 by Zimmerman and Leander [5]. 

Widely prescribed tranquillizers - diazepam, nitrazepam, etc. Medication with both opioid agonist and antagonist actions Herbal sedative drug, with various forms derived from different parts of the plant... 

Dondio, G., Ronzoni, S., Petrillo, P. Non-peptide S opioid agonists and antagonists, Exp. Opin. Ther. Patents 1997, 7, 1075-1098. 

Holzgrabe, U., Nachtsheim, C., Siener, T., Drosihn, S., Brandt, W. Opioid-Agonisten und -Antagonisten, Opioid-Rezeptoren (Opioid-agonists and -antagonists, opioid-receptors), Pharmazie 1997, 52, 4-22. 

Peptides with opioid agonistic and antagonistic activities... 

The reason for the irreversible opioid agonist and antagonist actions of 14-hydroxydihydromorphinone hydrazones (170, 171, and 172) has been attributed 261 to the formation of their respective azines (173). These azines, which may form if a large excess of hydrazine is not used during the synthesis of the hydrazones, have been found to be stable and to block opioid receptor binding in vitro irreversibly at 20-40 times the potency of their corresponding hydrazones. 

A hypothesis has been advanced to explain the different pharmacological response to opioid agonists and antagonists in terms of conformational differences about the basic center, as discussed in Chapter 13. However, a study by 13C-nmr of two such pairs (morphine-nalorphine, oxymorphone-naloxone) revealed little difference between agonist and antagonist molecules in either piperidine ring conformation (chairs only) or ratio of N- R axial to equatorial forms (83 17 for morphine, virtually 100% eq JV-R for 14-OH derivatives).035 ... 

Branson K R, Gross M E, Booth N H 1995 Opioid agonists and antagonists. In Adams H R (ed) Veterinary pharmacology and therapeutics. Iowa State University Press, Ames, lA, pp. 274-307... 

Representative opioid agonists and antagonists for p, 5, and k opioid receptors are listed in Table 1. 

Fiirst S, Hosztafi S, Friedmann T (1995) Structure-activity relationships of synthetic and semisynthetic opioid agonists and antagonists. Curr Med Chem 1 423-440... 

Botros S, Lipkowski AW, Larson DL, Stark AP, Takemori AE, Portoghese PS (1989) Opioid agonist and antagonist activities of peripherally selective derivatives of naltrexamine and oxymorphamine. J Med Chem 32 2068-2071... 

Dondio G, Ronzoni S, Petrillo P (1997) Non-peptide delta opioid agonists and antagonists. Exp Opin Ther Pat 7 1075-1098... 

The fifth chapter, Nonpeptidic 8 Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class What Have We Learned by Silvia N. Calderon, presents the major advances in the field of 8-opioid ligands and the extensive research performed to uncover the SAR of SNC-80 derivatives. Furthermore, synthetic methods are described for these compounds. 

Nonpeptidic Delta (8) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class What Have We Learned . 121... 

Structure activity relationships of synthetic and semisynthetic opioid agonists and antagonists... 

One major avenue of investigation in the field of opioid agonist and antagonist molecules involves the development of opioid analogues that penetrate the blood-brain-barrier (BBB) In fact inadequate blood-brain barrier (BBB) permeation can be responsible for low analgesic potencies. 

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