1 The pharmacological properties of the novel diarylacetamide .c-opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting K agonist) and ICI 204448 (a peripherally-selective Kc agonist).2 EMD 61753 binds with high affinity (IC50 5.6 nM) and selectivity (K:ft:6:a binding ratio 1:536:125:> 1,786) to ic-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for K-opioid receptors (rabbit vas deferens preparation). 3 Systemically-applied ['4C]-EMD 61753 is found in high concentrations in the lungs, liver, adrenal glands and kidneys. Considerably less radioactivity is detected in the whole brain, and this radioactivity is concentrated in the region of the cerebral ventricles in the choroid plexuses. EMD 61753 penetrates only poorly into the CNS. 4 EMD 61753 was weakly effective in pharmacological tests of central activity. This compound reversed haloperidolol-induced DOPA accumulation in the nucleus accumbens of the rat only at a dose of 30mgkg-', s.c., (doses of 0.1, 1.0 and 10mgkg-', s.c., and 1.0, 10 and 100mgkg-', p.o., were inactive). Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg-', s.c., and 100 mg kg-', p.o., whereas the motor performance of rats in the rotarod test was impaired by EMD 61753 with an IDm, value of 453 mg kg-', s.c.5 EMD 61753 produced dose-dependent, naloxone-reversible antinociception in the mouse formalin test (1st phase ID50 1.9 mg kg-', s.c., and 10.4mg kg-', p.o.; 2nd phase IDm 0.26mg kg', s.c., and 3.5 mg kg-', p.o.) and rodent abdominal constriction test (ID50 mouse 1.75 mg kg-', s.c., and 8.4mg kg-', p.o.; IDs rat 3.2mg kg', s.c., and 250mg kg', p.o.). EMD 61753 was inactive, or only weakly effective, in the rat pressure test under normalgesic conditions. After the induction of hyperalgesia with carrageenin, however, this compound elicited potent, dose-dependent (IDs 0.08 mg kg-', s.c., and 6.9 mg kg-', p.o., after remedial application, and 0.2 mg kg-', s.c., and 3.1 mg kg-', p.o., after prophylactic application) and naloxone-reversible antinociception. The antinociceptive action of systemically-applied (50 mg kg-', p.o.) EMD 61753 in the hyperalgesic pressure test was completely inhibited by injection of the K-opioid antagonist norbinaltorphimine (100 Lg) into the inflamed tissue, a result which indicates that this opioid effect is mediated peripherally. 6 Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was dose-dependently inhibited by systemically-applied EMD 61753 (ID13 values 3.7 mg kg', s.c., and 35.8 mg kg', p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphimine (50 pg). Extravasation elicited by the intraplantar application of substance P (10 pg) was not influenced by the administration of EMD 61753.7 EMD 61753 produced dose-dependent diuresis in non-hydrated rats at doses of and above 1.0 mg kg-', s.c., and 10 mg kg-', p.o., and in saline-loaded ra...

1 Studies with knockout mice lacking mdr1a P-glycoprotein (P-gp) have previously shown that blood-brain barrier P-gp is important in preventing the accumulation of several drugs in the brain. 2 Asimadoline (EMD 61753) is a peripherally selective k-opioid receptor agonist which is under development as a therapeutic analgaesic. From the structural characteristics of this drug and its peripheral selectivity, we hypothesized that it is transported by P-gp. 3 Using a pig-kidney polarized epithelial cell line transfected with mdr cDNAs, we demonstrate that asimadoline is transported by the mouse mdr1a P-gp and the human MDR1 P-gp. 4 Furthermore, we show that in mdr1a/1b double knockout mice, the absence of P-gp leads to a 9 fold increased accumulation of asimadoline in the brain. In line with this accumulation di erence, mdr1a/1b (7/7) mice are at least 8 fold more sensitive to the sedative e ect of asimadoline than wild-type mice. 5 Interestingly, the oral uptake of asimadoline was not substantially altered in mdr1a/1b (7/7) mice. 6 Our results demonstrate that for some drugs, P-gp in the blood-brain barrier can have a therapeutically bene®cial e ect by limiting brain penetration, whereas at the same time intestinal Pgp is not a signi®cant impediment to oral uptake of the drug.

Key Words: Atypical Neuroleptic-Clozapine-Dopamineantagonist-EMD 57445-Haloperidol-Panamesine-Schizophrenia-Sigma ligand.According to the classic dopamine (DA) hypothesis of schizophrenia, neuroleptic drugs must bind to the DA D, receptor. In addition several neuroleptic drugs, including the typical neuroleptic haloperidol and the atypical neuroleptic clozapine, exhibit high affinity to other receptors (13.26). Haloperidol particularly exhibits its highest affinity to the sigma site (25), which is distinct from the classical opiate or phencyclidine sites. Functional connections between sigma receptors and dopaminergic neurons in mesolimbic and cortical areas have been identified (5,7,14,19,41,43), and the involvement of sigma sites in the action of antipsychotic drugs has been shown in animal experiments (5,24,28). Further evidence for the significance of sigma sites in schizophrenia comes from investigations that benzomorphans cause symptoms that resemble schizophrenia in humans (20). Finally, several post-mortem studies have shown that the number of sigma binding sites in cortical and cerebellar regions is reduced in schizophrenic patients (37,38,44). Some attempts have been made to develop novel antipsychotic drugs with selective affinity for the sigma receptor (9,16,17,22,33,39) that would not have the extrapyramidal side effects (EPS) common to classic neuroleptics (25). Among these drugs rimcazole (17.18) initially has been shown to have some efficacy in humans (8,ll). Such drugs do, however, have EPS potential, and selective sigma ligands have ultimately not shown convincing antipsychotic efficacy in clinical trials (26). Drugs with greater selectivity (for sigma receptor subtypes) or drugs with higher intrinsic activity still must be developed (12,15,42). EMD 57445 was selected from a series of compounds that bear few structural

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