DESIGN OF POTENT DYNORPHIN A-(1-9) ANALOGS DEVOID OF SUPRASPINAL MOTOR EFFECTS IN MICE

Four analogues of dynorphin (Dyn) A-(1-9) incorporating D-Leu in posit ion 8 alone or in combination with the nonhydrolysable psi[CS-NH] thio peptide bond surrogate between positions 6 and 7 were tested in vitro for their ability to compete with the binding of selective kappa, mu, and delta opioid ligands, using membrane preparations of guinea pig ce rebellum (kappa) and rat brain (mu and delta), for their ability to bl ock the electrically induced contractions of the guinea pig ileum, and for their in vivo antinociceptive (writhing test) and motor (motor dy sfunction assay) activities in mice. [D-Leu(8)]Dyn A-(1-9) displayed a n affinity and a selectivity for the kappa opioid receptor that were c omparable with those of Dyn A-(1-9). The potencies of [D-Leu(8)]Dyn A- (1-9) in the guinea pig ileum, writhing, and motor dysfunction assays were markedly enhanced (8-12 fold) compared with those of Dyn A-(1-9). [(6) psi(7)(CS-NH),D-Leu(8)]Dyn A-(1-9), [Lys(6),(6) psi(7)(CS-NH),D- Leu(8)]Dyn A-(1-9), and [Leu(6),(6) psi(7)(CS-NH),D-Leu(8)]Dyn A-(1-9) were somewhat less potent than [D-Leu(8)]Dyn A-(1-9) in all opioid as says. However, the thiopeptides were more potent analgesics than Dyn A -(1-9) (ED50 of 29.5, 23.9, and 15.5 nmol/mouse, respectively,compared with 90.7 nmol/mouse for Dyr A-(1-9)) and caused little or no motor i mpairment at analgesic doses.