Beckett And Casy Model

R Compound t-butyl Buprenorphine CH3 Diprcnorphine

* Actually hydrogénation is carried out before the Grignard reaction. ** Cyanogen bromide N-demethylatcs the compounds. *** NaOH selectively cleaves the phenolic ether.

Figure 5-12. The oripavine compounds.

not to affect the tertiary OH) resulted in corresponding phenolic compounds with extremely high potency. The most astounding compound, etorphine (Fig. 5-12), revealed potencies up to 10,000 times that of morphine in animal models. It is interesting that in doses higher than required to produce analgesia (but still small) etorphine is capable of immobilizing even large animals. It soon became widely used in animal conservation efforts requiring the safe capture of animals as large as elephants in the wild.

As extraordinary as these potencies were, these N-methyl compounds exhibited full opiate agonist properties including, unfortunately, addiction liability. The next logical step would be to replace the methyl on the nitrogen atom with the substituents that have afforded either antagonists and/or mixed agonist/antagonists with other morphine-type structures. Although various groups were utilized, the cyclopropylmethyl function yielded the most interesting drugs. Thus the "thebaine adduct" (Fig. 5-12) is hydrogenated to produce a saturated ethano bridge function. Cyanogen bromide (von Braun reaction) N-demethylates the product; the NaOH/ethylene glycol procedure cleaves the phenolic methoxy function. Finally, cyclopropylmethyl bromide realkylates the nitrogen. Diprenorphine, where R = CH3, is not surprisingly, a "pure" antagonist devoid of analgetic action. Although also a potent antagonist, the R = ethyl homolog exhibits strong analgesia (at least in one screening test). The n-propyl and n-butyl members of this series were primarily potent agonists. Branching of the R group, however, led to increased antagonism; the terf-butyl compound, buprenorphine (BP, Buprenex) (Fig. 5-12), finally being 50 times more analgetic than morphine and, in the rat, at least, appearing not to have antagonist properties. In the mouse, however, BP showed strong antagonist properties. The high potency of these compounds and the contradictory pharmacology as to agonism, antagonism, or a mixture of these illustrates the difficulties of evaluating these drugs and, much less satisfactorily, explaining these apparent anomalies at this time. Even more interesting, as well as clinically significant, is BP's effect on gastrointestinal motility and respiration in humans. It is particularly important that the drug's effect on respiratory depression actually decreases as the dosage increases. This may represent an increased safety level. It is also of interest that BP, because of its high Iipophilicity, has a slow onset—and long duration of action. If, as suspected, this represents a slowness of opiate receptor binding (not weak affinity) and a resultant slow dissociation value, it may help explain the apparent lack of dependence potential encountered to date. One supportive piece of evidence for the slow drug-receptor dissociation is that while respiratory depression that BP may cause can be prevented by preadministering naloxone, it is difficult to reverse it even with high doses of naloxone, if the depression is produced first.

The discovery that it is an opiate antagonist—nalorphine also had agonist, and therefore analgetic, properties—failed to prove or disprove the original question of that early study. Was it possible to determine the pharmacological effects of mixing an agonist and antagonist in a single dose and find an optimum ratio for these two drugs that will retain potent analgesia while preventing the development of dependence, tolerance, and even abuse? The demonstration of opiate receptors and their subtypes (see later), the development of methodology to determine their regional brain distribution, and the ability to study differentially the binding capacities of agonist and antagonists to them, have combined to enable us to answer such a question with some sophistication.

The drug that may answer this question is currently undergoing clinical evaluation as an analgetic for postoperative pain.

The racemate of picenadol exhibits agonist/antagonist properties. However, it was shown that the dextrorotary isomer possesses agonist, and the levo enantiomer the antagonist activity, with some weak agonism. The analgetic action could be shown to result from strong binding of the (+)-isomer to the |i receptor, probably with some contribution from the weak agonist activity of the (-)-isomer. The isomers of the racemate were shown to possess a n/8 ratio of 1.0 for the dextro-isomer, and 0.5 for the /evo-isomer. K-Receptor activity could not be demonstrated for either optical form.

Both morphine and picenadol exhibited the expected profile of opiate-type side effects in human subjects. It is surprising, however, that naloxone reversed these only in the case of morphine. It is also of interest that picenadol possesses a higher affinity for the (i-opi-ate receptor than does morphine. The antagonist activity of the racemate (presumably from the /evo-isomer) gives the drug a lesser propensity to produce significant respiratory depression than does morphine. Preclinical animal studies demonstrated that picenadol





Figure 5-13. Optical isomerism and biological activity.

did not suppress morphine withdrawal symptoms; neither did it initiate them. These and other differences between morphine and picenadol have been explained on the basis of binding-site differences as well as the anticholinergic activity of the latter drug. More extensive human trials will establish whether picenadol will offer any clinical advantages over morphine.

5.11. The Opiate Receptor

The existence of binding sites specific to opiates had been assumed for many years. Some of the early "indirect" evidence leading to this receptor hypothesis included the relatively high potency of the narcotic drugs and the structural and stereospecificity exhibited by them. Even with the synthetic analgetics biological effects are usually found in those optical isomers stereochemically related to the natural (-) morphine molecule.12

The concept involved here may be understood by considering Figure 5-13. It will be recalled that enantiomers are nonsuperimposable mirror image structures in which all interatomic distances are the same. If a three-point interaction between a drug and its receptor is assumed, it can be seen that only in "drug" A is the configuration correct to bind all three groups (X, Y, Z) to complementary areas on the receptor surface. It can be said that the receptor can "distinguish" between the two isomers.

The fact that apparently small changes in structures (specifically around the nitrogen atom) resulted in very specific and effective opiate antagonists, of course, added to the strength of the receptor concept.

Beckett and Casy (1954) made the first proposal for the analgetic receptor (Fig. 5-14) based on a detailed study of the geometric features of most morphine-type drugs known then, including morphinans, meperidine, and methadone-type compounds. With later updating (Casy, 1975) the proposal included an anionic site interacting with the cationic (protonated) nitrogen atom; a flat surface accommodating the planar aromatic ring, and a cavity site accommodating the C-15-C-16 carbon atoms of the piperidine ring. The tremendous increases in analgetic potency encountered with the oripavines (e.g., etor-phine) would necessitate the addition of a stereospecific lipophilic site to the Beckett-Casy model. The C-19 3° alcohol function may provide additional hydrogen bonding to the receptor's proteinaceous topography, or, alternatively, to the C-6 methoxy group, locking

12 When (+) morphine was synthesized, it was found to be devoid of analgesia.

Beckett And Casy Model
Figure 5-14. Relationship of morphine to Beckett-Casy receptor.

in a very favorable conformation. The aliphatic (or aralkyl) functions on C-19 (R group, Fig. 5-12) would provide the extra receptor-binding capacity to the lipophilic site, thus possibly accounting for the quantum jump in potency. The significance of this lipophilic site would shortly be confirmed with the discovery of the natural ligands for these then-still-putative receptors—the enkephalins (see later).

With the discovery of stereospecific opiate binding sites in rat brain homogenate by several groups (Pert and Snyder, 1973b; Simon et al., 1973), the existence of pharmacologic opiate receptors was put on a sound scientific footing. Additional supportive evidence was produced by determining the relative effectiveness of known agonist analgetics, antagonists, and mixed agonists/antagonists in reducing the stereospecific binding of tritium-labeled naloxone at rat brain sites (actually rat brain homogenates) (Table 5-6). The pharmacologi-

Table 5-6. Relative Potencies of Drugs in Reducing Stereospecific 3H-Naloxone Binding to Rat Brain Homogenate


ED50 (nMy

No effect at 0.1 mM


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