(D‐Phe¹²) bombesin and substance P analogues function as central bombesin receptor antagonists

Abstract

The potency of synthetic bombesin (BN) analogues with D-Phe12 substitutions and substance P analogues was investigated in the rat CNS. (D-Phe12,Leu14)BN, (D-Phe12)BN and (Tyr4,D-Phe12)BN inhibited binding to rat brain slices with IC50 values of approximately 2 microM. Similarly, spantide inhibited binding to rat brain slices with an IC50 value of 1.5 microM. Spantide inhibited specific (125I-Tyr4)BN binding as a result of decreased rate of association, whereas the rate of dissociation was unaffected. Neither the (D-Phe12)BN analogues nor the substance P analogues inhibited specific binding of 125I-VIP to rat brain slices. Central administration of BN (0.5 micrograms) induced grooming and suppressed feeding and resting. (Tyr4, D-Phe12)BN (5 micrograms) antagonized the behavioral effects of BN. Although spantide (2 micrograms) also antagonized many of the BN effects, it had intrinsic effects and hence the behavioral antagonism was not specific. These data suggest that although both (D-Phe12)BN and substance P analogues may function as central BN receptor antagonists, the (D-Phe12)BN analogues may be functionally the more useful class of antagonists.

Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N‐terminal d‐Trp or d‐Tpi

“…Several classes of bombesin/GRP receptor antagonists have been described (23)(24)(25)(26)(27)(28)(29)(30). Early antagonists were analogs of substance P but they lacked specificity and were relatively weak (23)(24)(25).…”

“…Early antagonists were analogs of substance P but they lacked specificity and were relatively weak (23)(24)(25). Synthetic bombesin analogs based on substitution of D-Phe for His at position 12 in the bombesin molecule were more specific antagonists but were active only at relatively high (millimolar) concentration (26,27). More recently, several short chain analogs with a reduced peptide bond (CH,NH) between positions 13 and 14 were reported (28).…”

“…More recently, several short chain analogs with a reduced peptide bond (CH,NH) between positions 13 and 14 were reported (28). The newest class of bombesin receptor antagonists is represented by des-MetI4 analogs of the GRP (20)(21)(22)(23)(24)(25)(26)(27) or bombesin (6)(7)(8)(9)(10)(11)(12)(13)(14) which have demonstrable activity in the nanomolar concentration range (29-3 1). The newest class of bombesin receptor antagonists is represented by des-MetI4 analogs of the GRP (20)(21)(22)(23)(24)(25)(26)(27) or bombesin (6)(7)(8)(9)(10)(11)(12)(13)(14) which have demonstrable activity in the nanomolar concentration range (29-3 1).…”

“…GRP (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), used in concentrations from 0.1 to 30 nM, induced dose-dependent stimulation of amylase release from rat pancreatic acini (Fig. The mean basal amylase release was found to be 47.73 k 5.2pglrnL and it represented 2.23 I 0.2% (mean f SE, n = 15) of the total amylase content of the preparation.…”

Inhibition of Bombesin-Stimulated Gastrin Release from Isolated Human G Cells by Bombesin Analogs

“…The first group was initially developed as substance P antagonists, but because of the sequence homology between the two peptides these analogs also block the effect of BN [6,7]. The second group com prised [D-Phel2]BN analogs [8,9] and the third group included BN analogs with re duced peptide bonds [10]. These three classes of BN/GRP receptor antagonists have been shown to be potent inhibitors of BN-stimulated amylase secretion from dis persed pancreatic acini in all species investi gated.…”