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...

A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.

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Systematic structural modifications of indolealkylphenylpiperazines led to improved selectivity and affinity within this class of 5-HT(1A) receptor agonists. Introduction of electron-withdrawing groups in position 5 on the indole raises serotonin transporter affinity, and the cyano group proved to be the best substituent here. 5-Fluoro and 5-cyano substituted indoles show comparable results in in vitro and in vivo tests, and bioisosterism between these substituents was supported by calculation of the molecular electrostatic potentials and dipole moments. Compounds showing promising in vitro data were further examined in ex vivo (p-chloroamphetamine assay) and in vivo (ultrasonic vocalization) tests. Optimization of the arylpiperazine moiety indicated that the 5-benzofuranyl-2-carboxamide was best suited to increase 5-HT transporter and 5-HT(1A) receptor affinity and to suppress D(2) receptor binding. 5-[4-[4-(5-Cyano-3-indolyl)butyl]-1-piperazinyl]benzofuran-2-carboxamide 29 (vilazodone, EMD 68843) was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 1.1 nM] with subnanomolar 5-HT(1A) affinity [IC(50) = 0.2 nM] and as a subnanomolar 5-HT reuptake inhibitor [RUI = 0.5 nM] showing a great selectivity to other GPCRs (e.g., D(2), IC(50) = 666 nM).