Design of potent and selective dynorphin A related peptides devoid of supraspinal motor effects in mice

Dynorphin A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro (Dyn Ia) was previously shown to be a highly potent and selective kappa opioid peptide. Four analogs of Dyn Ia are synthesized by the solid-phase procedure, introducing pseudo CH2NH linkage between positions 6 and 7 as follows: analog 1, [6 psi 7 (CH2NH)]Dyn Ia; analog 2, [6 psi 7 (CH2NH), D-Leu8]Dyn Ia; analog 3, [N(Me)-Tyr1, 6 psi 7 (CH2NH)]Dyn Ia; and analog 4, [N(Me)-Tyr1, 6 psi 7 (CH2NH), D-Leu8]Dyn Ia. The purified peptides are compared in vitro with Dyn Ia for their ability to compete with the binding of selective kappa, mu, and delta opioid ligands using membrane preparations of guinea pig cerebellum (kappa) and rat brain (mu and delta). The synthetic compounds are also compared in vivo in mice (intracerebroventricularly administered) for their analgesic activity against acetic acid induced writhing and their ability to produce motor dysfunction. All compounds display a high affinity (Ki = 0.5-1.8 nM) and a good selectivity for the kappa opioid receptor, and their rank order of potency on the kappa site (analog 2 > analog 1 > analog 3 > analog 4) closely parallels their potency (AD50 = 1.57-5 nmol/mouse) in inhibiting acetic acid induced writhing in mice (analog 2 > analog 1 > analog 4 > analog 3). On the other hand, all the synthetic analogs are less potent than Dyn Ia in producing motor effects, analog 2 being the least potent (CD50 = 15.4 nM as compared with 2.9 nM for Dyn Ia).(ABSTRACT TRUNCATED AT 250 WORDS)