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Dopamine D3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D3-preferring antagonist PNU-99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU-99194A in two separate studies. However, four other putative D3-preferring antagonists (PD 152255, (+)-S14297, nafadotride and (+)-AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU-99194A, which has been suggested to induce a stimulus mediated specifically by D3 antagonism, the D3-preferring antagonist (+)-UH 232 and clozapine both induced full generalization. However, the PNU-99194A-trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU-99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However, in vitro receptor binding studies with M1-M5 receptors indicated that (with the possible exception of the M4 receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU-99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU-99194A had high affinity for the D3 receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU-99194A and muscarinic antagonists may be mediated by common effects 'downstream' from either muscarinic or D3 receptors; (2) D3 antagonism does not play a critical role in the clozapine stimulus (since D3-preferring antagonists did not consistently induce generalization to clozapine); (3) although D3 antagonism plays a role in the PNU-91994A stimulus (since the D3-preferring antagonist (+)-UH 232 induced full generalization, in accord with results from prior studies with other D3-preferring antagonists, the PNU-99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. The in vivo differences observed between PNU-99194A and other D3-preferring antagonists should be borne in mind when this agent is used as a tool to study D3 receptor functioning in vivo. The similarities between the PNU-99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU-99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU-99194A.

The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H- benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.

Three isoxazole bioisosteres of glutamic acid derived from the specific AMPA receptor agonist ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) were synthesized and tested electrophysiologically and in different receptor binding systems. ( RS )-2-Amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (trifluoro-AMPA, 8) showed more potent agonist activity (EC 50 2.3 μM) and lower affinity (IC 50 0.08 μM) for AMPA receptors than AMPA itself (EC 50 3.5 μM and IC 50 0.04 μM, respectively). Like AMPA, trifluoro-AMPA ( 8 ) did not bind significantly to N -methyl- d -aspartic acid (NMDA) receptor sites, but trifluoro-AMPA ( 8 ) was more potent as an inhibitor of [ 3 H]kainic acid ([ 3 H]KAIN) binding (IC 50 7.1 μM) than AMPA (IC 50 32 μM). ( RS )-2-Amino-3-(3-chloro-5-methyl-4-isoxazolyl)propionic acid ( 14 ), the 3-chloro analogue of AMPA, and the isomeric compound ( RS )-2-amino-3-(3-chloro-4-methyl-5-isoxazolyl)propionic acid ( 15 ), did not show significant neuroexcitatory effects at or affinities for AMPA, NMDA, or KAIN receptor sites.

Interest in the physiology and pharmacology of the dicarboxylic amino acids L-glutamate and L-aspartate originally stemmed from identification of the powerful excitatory actions of these amino acids in the motor cortex by Hayashi in 1954 (1) and in the spinal cord by Curtis and colleagues in 1960 (2). After a fairly prolonged period of doubt, excitatory amino acids (EAAs) have gradually become accepted as the major transmitter of fast excitatory signals in the mammalian central nervous system (eNS). The receptors mediating these actions have been classified into three subtypes based on the selective agonists N-methyl-D-aspartate (NMDA), quisqualate, and kainate (3-6). The recent rapid advances in this field have primarily re­ sulted from the identification and radiolabeling of potent and selective agonists and antagonists for elucidating the localization, density, ligand binding, and modulatory properties of these various subtypes of BAA re­ ceptors (7, 8). In particular, this approach has been very fruitful in the characterization of various sites associated with the NMDA receptor chan­ nel complex. This has complemented the powerful electrophysiological tech

Previous reports on a series of benzoylthiophenes, including PD 81,723 [2-amino-4,5-dimethyl-3-(3-trifluoromethyl-benzoyl) thiophene], have shown specific enhancement of agonist binding at the adenosine A1 receptor. We have studied the effects of two substituted benzoylthiophenes, PD 78,416 (thieno[2,3-c]pyridine-6(5H)-carboxylic acid, 2-amino-3-benzoyl-4,7-dihydro-ethyl ester) and RS-74513-000 [2-amino-4-ethyl-5-methyl-3-(3-trifluoro-methyl-benzoyl) thiophene] on response elicited by adenosine A1 receptors in isolated guinea pig left atrium and ileum. In the electrically paced left atrium, PD 78,416 antagonized negative inotropic effect elicited by the agonist CPA [N6-cyclopentyladenosine] with a pKB value of 6.2 +/- 0.2 (n = 4). At a low concentration which had no antagonistic effect (0.1 microM), PD 78,416 enhanced the effect of CPA. The concentration-response curve to CPA was shifted leftward by 5.1 fold (95% confidence limits 2.4-11.2). In field stimulated isolated ileum, PD 78,416 (0.1, 0.3, 1 microM) did not enhance or antagonize effects of CPA. At concentrations above 1 microM, PD 78,416 decreased electrically induced contraction. This effect was not sensitive to adenosine deaminase and was not antagonized by the A1 antagonist CPX [8-cyclopentyl-1,3-dipropyl-xanthine] (1 microM). Unlike PD 78,416, RS-74513-000 (0.01, 0.1, 1, 3, 10 microM) did not antagonize or enhance effects of CPA in the left atrium. However, effects of CPA in ileum were enhanced by RS-74513-000 (1 and 3 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

1. The muscarinic pharmacology of a novel oxadiazole muscarinic agonist, (+/-) L-660,863, [+/-3-(3-amino-1,2,4-oxadiazole-5-yl)-quinuclidine] has been studied using pharmacological, radioligand binding and biochemical techniques, in vitro. 2. In isolated tissue experiments, (+/-)L-660,863 was a more potent agonist than carbachol in all preparations studied, being most potent at muscarinic receptors mediating negative chronotropy in guinea-pig right, spontaneously beating atria and least potent at receptors mediating contractions in canine saphenous vein and endothelial denuded rabbit aorta (-log EC50 values were 8.8, 6.6 and 6.3, respectively. The apparent affinities (-log KA) of (+/-)L-660,863) estimated by receptor inactivation, showed some selectivity toward the atrial M2 muscarinic receptor (-log KA = 7.6) in comparison to the M1 or M3 muscarinic receptors (-log KA = 5.4 and 6.2) respectively. This degree of selectivity was also observed in competition radioligand binding studies. 3. At M3 muscarinic receptors mediating inositol phosphates (IPs) accumulation in longitudinal muscle of guinea-pig ileum, the potency of (+/-)L-660,863 (-log EC50 value = 6.2) was similar to the apparent affinity calculated at M3 muscarinic receptors in the functional studies (see above). In contrast, at muscarinic receptors mediating IPs accumulation in guinea-pig atria and ventricles, the potency for (+/-)L-660,863 (-log EC50 = 6.2 and 6.4, respectively) was lower than the apparent affinity calculated at M2 muscarinic receptors from inotropic and binding studies in cardiac tissue (see above).(ABSTRACT TRUNCATED AT 250 WORDS)

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) acts by increasing chloride permeability in the postsynaptic cell membrane. Chloride ion channels are regulated via GABA binding to its receptor. The cellular response to GABA has been shown to be enhanced by benzodiazepine and barbiturate drugs. This potentiation of GABA-mediated inhibition may explain much of the nervous system depressant action of these clinically important agents.