DESIGN OF POTENT AND SELECTIVE DYNORPHIN-A RELATED PEPTIDES DEVOID OFSUPRASPINAL MOTOR EFFECTS IN MICE

Dynorphin A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro (Dyn Ia) was previously sho wn to be a highly potent and selective kappa opioid peptide. Four anal ogs of Dyn Ia are synthesized by the solid-phase procedure, introducin g pseudo CH2NH linkage between positions 6 and 7 as follows: analog 1, [6psi7 (CH2NH)]Dyn Ia; analog 2, [6psi7 (CH2NH), D-Leu8]Dyn Ia; analo g 3, [N(Me)-Tyr1, 6psi7 (CH2NH)]Dyn Ia; arid analog 4, [N(Me)-Tyr1, 6p si7 (CH2NH), D-Leu8]Dyn Ia. The purified peptides are compared in vitr o with Dyn la for their ability to compete with the binding of selecti ve kappa, mu, and delta opioid ligands using membrane preparations of guinea pig cerebellum (kappa) and rat brain (mu and delta). The synthe tic compounds are also compared in vivo in mice (intracerebroventricul arly administered) for their analgesic activity against acetic acid in duced writhing and their ability to produce motor dysfunction. All com pounds display a high affinity (K(i) = 0.5-1.8 nM) and a good selectiv ity for the kappa opioid receptor, and their rank order of potency on the kappa site (analog 2 > analog 1 > analog 3 > analog 4) closely par allels their potency (AD50 = 1.57-5 nmol/mouse) in inhibiting acetic a cid 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 la in producing motor effects, analog 2 being the least potent (CD 50 = 15.4 nM as compared with 2.9 nM for Dyn Ia). Thus, analog 2 is a good model for developing Dyn A related peptides with selective antino ciceptive activity.