An approach to the self regulatory mechanism of substance P actions: II. Biological activity of new synthetic peptide analogs related both to enkephalin and substance P.

Analogs of substance P in which the N-terminal part of native peptide was replaced by an enkephalin active fragment have been synthesized. We found this peptide to be as active as substance P on the GPI test. The analogs were completely inactive on GPI opiate test; the opiate activity was observed on MVD and RVD tests. Surprisingly, we found that SP-activity was reduced by naloxone.

An approach to the elucidation of self-regulatory mechanism of substance P action. I. Synthesis and biological properties of pentapeptides related both to the substance P C-terminal fragment and enkephalins.

Seven pentapeptides, chemically related both to C-terminal fragment of substance P and Met-enkephalin were synthetized and their pharmacological properties were investigated. Peptides I-VI (L-amino acid residue in position 2) antagonized the inhibitory action of D-Ala2-Met-EK-NH2 on isolated vas deferens in vitro but were devoid of opiate-receptor binding activity in radioreceptor studies. Peptide VII (D-Phe2-Met-EK-NH2) exerted a weak inhibitory effect on contractions of transmurally stimulated vas deferens of rat which was abolished by naloxone (10(-8) M) and showed relatively strong but short-lasting analgesic activity in vivo. This peptide at concentration above 10(-5) M partially displaced the 3H-naloxone from its binding sites in striatal membranes. The possible existence of the neuronal substance P-enkephalin self-regulatory mechanism is discussed.

Analgesic activity and opiate receptor affinity of new derivatives of N-butylpiperidine.

The three newly synthesized derivatives of N-butylpiperidine 1-butyl-4-phenyl-4-isonicotinoylaminoethylpiperidine (BG 25), 1-buty-isonicotinoylpiperidine (BG 26) and N-(1-butyl-4-phenyl-4-piperidinoyl) tetrahydropapaverine (BG 9) were evaluated for analgesic activity and opiate receptor affinity. All the three compounds showed analgesic activity both in hot-plate and flinch-squeak-jump test in mice, BG 9 being the most potent. The affinity of the compounds to opiate receptor was moderate (in comparison with pentazocine): the affinity of BG 9 was much greater than that of BG 25 and BG 26. The compounds showed a pronounced inhibitory action in stimulated guinea-pig ileum preparation; this was reversible by naloxone. As evaluated on pA basis, all three investigated compounds showed moderate antagonistic activity. Also in this respect BG 9 was more active than the other two compounds. Cholinolytic and strong spasmolytic properties were observed in isolated rat ileum preparation for BG 9 only.