Benzomorphans affinity

It has been proposed, on the basis of observations made using the benzo-morphan derivative (MR 2034) (8), that all kappa agonists may cause undesired dysophoria and even psychotomimesis in man [27]. Benzomorphans such as MR 2034 with affinity for sigma receptors are well-known to be associated with dysphoria. To date, there has been no report of a dose-ranging clinical study with a truly kappa selective agonist which describes the analgesic effects and the onset of dysphoric symptoms. 

However, the above-mentioned benzomorphans and morphinans are not the only compounds reported to have affinity for both the NMDA receptor and the p-opioid receptor. There have been several reports on the NMDA... 

Opioid receptor affinity labels have been reported for other narcotic analgesics, for example, piperidines, 293 294 benzomorphans, 295 296 and mor-phinans, 297,298 and the topic is further discussed in Chapter 13 (p. 445). Not only is the oxo-function in the 4,5-epoxymorphinan C-ring available for ready elaboration, but C-6 substituents, although they affect agonist potency, do not impair unduly receptor affinity. 299 301 ... 

N-(2,4,5-Trihydroxyphenethyl)normetazocine was prepared by the NIH group(76) from normetazocine as a potential, irreversible, opioid-receptor inhibitor. This is, in effect, a 6-hydroxydopamine benzomorphan analog that unfortunately had only a weak affinity for the opioid receptor. 

TABLE III. ANTAGONIST POTENCY AND BINDING AFFINITY OF BENZOMORPHANS WITH VARYING N-SUBSTITUENTS AND THEIR ENERGIES OF INTERACTION WITH MODEL ANIONIC RECEPTOR SITES. ... 

Antagonist potencies measured in vitro in the guinea pig ileum system or in vivo by extent of withdrawal in addicted animals should closely parallel the affinity of opiates for the receptor site. Both antagonist potencies and stero-specific binding constants have been measured for a number of N-substituted 5,9 dimethyl 2 hydroxy 6,7 benzomorphan analogues (14, 15, 32). Table III gives these values for the compounds studied and shows the extent of correlation between the known affinities and potencies for four analogues. 

Table 7.10 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Benzomorphan Derivatives and TRK-820 ...

A series of analogs of the benzomorphans were prepared in which the amino group is exocyclic (99 and 100) (401). In contrast to the benzomorphans and other rigid opiates, the receptor binding of (99) and its analogs exhibits almost no stereoselectivity [K- (jit) = 2.0 and 2.2 nAf for the (+) and (-) isomers] in vivo, both isomers of (99) were inactive. Racemic (100) exhibits an almost 10-fold increase in K-receptor affinity (K = 6.6 nAQ compared to that of the isomers of (99) while retaining nanomolar affinity for ix receptors = 2.0 nM) this compound is a full k agonist in vivo. 

The common features of the local anaesthetic receptor site suggest that novel Na channel blocking drugs could be developed to fit this site that might have higher affinity and specificity than presently available compounds. Consistent with this idea, the novel compound Bill 890 CL, a complex ether of benzoyl and modified benzomorphan moieties, is a potent Na channel blocker binding at the local anaesthetic receptor site with a of 50 nM for the inactivated state (Carter et al 2000). It is aimed for neuroprotective therapy in the treatment of stroke and possibly neurodegenerative diseases. 

Ten years ago, when this project began in the Parke-Davis Laboratories there were a number of chemical structures reported in the literature as possessing high affinity for the kappa opioid receptor. Some of these are shown below (fig. 1). They include the endogenous peptide, dynorphin, the benzomorphan derivative EKC, the benzodiazepine tifluadom, and the 1,2 aminoamide U-50488. 

A classification scheme has been suggested. Those receptors that bind the (-F )-6,7-benzomorphans, such as (-F)-NANM and (-F )-Pentazocine, with high affinity and those which bind these ligands with low affinity are designed as CT, and CTj respectively (Quirion et al., 1992). Other sites with a distinct pharmacological profile versus the previously defined subtypes appear to exist. A series of l-phenyl-3-aminotetralines (PATs), exemplified by Hj-PAT was found to stimulate tyrosine hydroxylase activity and dopamine synthesis through interaction with a novel aj receptor (Wyrick and Booth, 1995). 

Keywords Morphinans Benzomorphans Kappa, delta and mu receptor affinity... 

Neumeyer, J.L., Bidlack, J.M., Zong, R., Bakthavachalam, V., Gao, P., Cohen, D.J., Negus, S.S., Mello, N.K., 1999. Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives. Mixed kappa agonists and mu agonists/antagonists as potential pharma-cotherapeutics for cocaine dependence. J. Med. Chem. (in press). 

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