| Abstract
| - A total of 32 compounds was prepared to investigate the functional role of Phe4 in NC(1−13)-NH2, the minimal sequence maintaining the same activity as the natural peptide nociceptin.These compounds could be divided into three series in which Phe4 was replaced with residuesthat would (i) alter aromaticity or side chain length, (ii) introduce steric constraint, and (iii)modify the phenyl ring. Compounds were tested for biological activity as (a) inhibitors of theelectrically stimulated contraction of the mouse vas deferens; (b) competitors of the binding of[3H]-NC-NH2 to mouse brain membranes; and (c) inhibitors of forskolin-stimulated cAMPaccumulation in CHO cells expressing the recombinant human OP4 receptor. Results indicatethat all compounds of the first and second series were inactive or very weak with the exceptionof [N(CH3)Phe4]NC(1−13)-NH2, which was only 3-fold less potent than NC(1−13)-NH2.Compounds of the third series showed higher, equal, or lower potencies than NC(1−13)-NH2.In particular, [(pF)Phe4]NC(1−13)-NH2 (pF) and [(pNO2)Phe4]NC(1−13)-NH2 (pNO2) were moreactive than NC(1−13)-NH2 by a factor of 5. In the mVD, these compounds showed the followingorder of potency: (pF) = (pNO2) ≥ (pCN) > (pCl) > (pBr) > (pI) = (pCF3) = (pOCH3) > (pCH3)> (pNH2) = (pOH). (oF) and especially (mF) maintained high potencies but were less activethan (pF). Similar orders of potency were observed in binding competition and cAMPaccumulation studies. There was a strong (r2 ≥ 0.66) correlation between data observed inthese assays. Biological activity data of compounds of the third series were plotted againstsome Hansch parameters that are currently used to quantify physicochemical features of thesubstituents. In the three biological assays agonist potency/affinity positively correlates withthe electron withdrawal properties of the groups in the p-position of Phe4 and inversely withtheir size.
|
