MVD assay

In 1992, it was reported that Boc-Tyr-Pro-Gly-Phe-Leu-Thr-OH, an opioid peptide lacking a positive charge, showed weak 5-antagonist potency (K.e = 560 nM) in the MVD assay [20]. Subsequently, it was shown that a derivative of this peptide containing an O-t-butyl-protected Thr6 residue, Boc-Tyr-Pro-... 

The first known compound with a mixed p-agonist/6-antagonist profile was the tetrapeptide amide H-Tyr-Tic-Phe-Phe-NH2 (TIPP-NH2) [27] (Table 3). TIPP-NH2 was a moderately potent p-agonist in the GPI assay and a potent 6 antagonist in the MVD assay. It showed some 6- versus p-receptor... 

GPI assay IC50 [nM] MVD assay Ke [nM]" Receptor binding assays6 ... 

Several nonpeptidic 6-opioid agonists have been synthesized, although none are currently available clinically. These include BW373U86 which is —10 and 20 times more selective for 6-opioid receptor over the p and kappa opioid receptor, respectively, in receptor-binding assays [18]. BW 373U86 also demonstrated high potency (ED50 of 0.2 0.06 nM) in the MVD assay, and its... 

Early SAR investigations revealed that the amide of Met-enkephalin was several times as active as the parent with a longer duration of action and that replacement of Gly2 by D-Ala had a similar influence on peptide stability/62,63 It was later shown that a variety of D-amino acids in place of Gly2 caused a marked increase in potency both in GPI and MVD assays, results presumed... 

The potency of [d-Ala2]Leu-enkephalin in GPI and MVD assays is differentially altered when L-Leu is replaced by the D-amino acid, [D-Ala2-D-Leus]enkephalin (DADL) is half as effective as the parent in the ileum test but three times more active in the MVD procedure (see data)(57) DADL is now commonly employed as a selective 5-agonist (see p 356) Thus,... 

Among the compounds in Table 3, compound 5 showed the highest antitussive activity however, it showed a markedly reduced 5 receptor antagonist activity in the mouse vas deferens (MVD) assay (Table 4). In the MVD assay, the Ke value indicated the potency of the test compound antagonist activity for each receptor type. Compound 5 showed a markedly high Ke value (low potency) for the 8 receptor compared with that of unmodified NTI [39]. Moreover, compound 5 showed a reduced selectivity for the 8 receptor over the p and k receptors. This suggested that the antitussive activity of compound 5 may be induced by its active metabolites (e.g., 3-OH analog). 

The opioid receptor selectivity of TRK-851 was tested in the MVD assay (Table 9). TRK-851 strongly antagonized the agonist activity of DPDPE (8), and it showed over 200 times greater selectivity for the 5 opioid receptor than for p or k receptors. These results strongly suggested that the antitussive effect of TRK-851 was derived from its marked antagonism of 5 opioid receptors [6]. 

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