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

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 μM. Similarly, spantide inhibited binding to rat brain slices with an IC₅₀ value of 1.5 μM. 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 μg) induced grooming and suppressed feeding and resting. (Tyr⁴, D‐Phe¹²)BN (5 μg) antagonized the behavioral effects of BN. Although spantide (2 μg) 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.