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A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.

An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.

The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.

At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.

Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo.

This communication reports SARs for the first orexin-1 receptor antagonist series of 1-aryl-3-quinolin-4-yl and 1-aryl-3-naphthyridin-4-yl ureas. One of these compounds, 31 (SB-334867), has excellent selectivity for the orexin-1 receptor, blood-brain barrier permeability and shows in vivo activity following ip dosing.

Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).

Starting from the dopamine D3 receptor antagonist SB-277011 1, a series of 2,3,4,5-tetrahydro-1H-3-benzazepines has been identified with high affinity for the dopamine D3 receptor and selectivity over the D2 receptor. The 3-acetamido-2-fluorocinnamide derivative 20 gave high D3 receptor affinity (pKi 8.4) with 130-fold selectivity over the 2, receptor.

SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.

SAR studies around a series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides, identified by high-throughput screening at the novel SB-204269 binding site, have provided compounds such as 13, 29-33 with high affinity and excellent anticonvulsant activity in animal models.

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.

A novel series of 5,6,7,8-tetrahydroquinazolines, 4,5,6,7-tetrahydroindazoles and 4,5,6,7-tetrahydrobenzothiazoles has been prepared, having high affinity and selectivity for the dopamine D3 receptor. The 4-methoxy-5,6,7,8-tetrahydroquinazoline 6i and 2-amino-4,5,6,7-tetrahydrobenzothiazole 8 proved to be agonists with among the highest D3 receptor affinities and selectivities reported to date.

Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.

Optimisation of novel cis- and trans-4-(substituted-amido)benzopyran-3-ol derivatives has led to the identification of SB-220453 20 with an in vivo pre-clinical CNS profile predictive of potential antimigraine activity.

A series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides was identified by high-throughput screening at the novel SB-204269 binding site. SAR studies have provided compounds 4 and 14 with high affinity and good anticonvulsant activity in animal models.

Starting from a series of 2-aminotetralins 1, a novel series of N-[4-(4-phenylbenzoylamino)butyl]-octahydrobenzoquinolines and hexahydrobenzoindoles with high potency and selectivity for the dopamine D3 receptor has been designed. The effect of ligand chirality on binding affinity has been established. Selected derivatives (e.g. 2o, 2p) show high functional selectivity and enhanced in vivo properties compared to 1.

Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.

The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.

The synthesis and antihypertensive activity of a series of novel 3-[(substituted-carbonyl)amino]-2H-1-benzopyran-4-ols, administered orally to spontaneously hypertensive rats, are described. Optimum activity in this series was observed for compounds with branched alkyl or branched alkylamino groups flanking the carbonyl or thiocarbonyl group (21, 31-33), which were approximately equipotent to cromakalim. Replacement of the 4-hydroxyl group by hydrogen, methoxy, or amino in this series only led to a slight reduction in potency. These observations are in marked contrast to the structure-activity relationships previously found for the 4-amidobenzopyran-3-ols. The antihypertensive activity of representative compounds 15 and 33 was attempted by preatreatment with glibenclamide, and thus these compounds may belong to the series of drugs which have been classified as potassium channel activators.

The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents. This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor. Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system. These compounds generally show improved affinity relative to the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine. Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.

The substituted benzamides are used clinically both as antipsychotics and as stimulants of gastric motility. The antipsychotic effects are considered to be a consequence of their central dopamine antagonist properties, but there is evidence that the gastric stimulatory effects may be mediated by other mechanisms. Clebopride (3) is a substituted benzamide that although marketed for its stimulatory effects on gastric motility, is also a potent central dopamine antagonist. The corresponding anilide, BRL 20596 (4a), where the amide bond has been reversed, has been synthesized and found to lack gastric stimulatory activity. However, the potent central dopamine antagonist activity is retained, suggesting that benzamides and anilides have similar affinities for central dopamine receptors. The implications of the conformations adopted by benzamides and anilides at such receptors are discussed. Evidence is also presented that there is a further lipophilic binding site on such receptors for which the N-benzyl group is an optimal fit.

Following the discovery that 3-(dimethylamino)-1,1-diphenyl-2-propanol hydrobromide (1) possesses potent reserpine-prevention activity in mice, a series of analogues of 1 was synthesized and evaluated as potential antidepressant agents. Several routes to analogues of 1 were evaluated, the most generally applicable of which was the regiospecific ring opening of a suitably functionalized 1,1-diaryl-2,3-epoxypropane (obtained in three stages from the corresponding benzophenone) with the appropriate amine. The more interesting compounds of the series were evaluated for their propensity to cause undesirable peripheral anticholinergic effects, all compounds tested being markedly less active than imipramine on this parameter. On the basis of its good activity in biochemical and pharmacological animal models of depression, together with its relative lack of anticholinergic side effects, 1-(3-chlorophenyl)-3-(dimethylamino)-1-phenyl-2-propanol hydrochloride (20, BRL 14342) was chosen for further evaluation.

The substituted benzamides metoclopramide (1) and clebopride (3) are stimulants of gastric motility. They are also central dopamine receptor antagonists with 3 being the more potent. This is presumed to be due to an additional interaction of its N-benzyl group with the receptor. The effect of restricting the conformation of this group by replacing the N-benzylpiperidine side chain of 3 by phenyl-substituted quinolizidines and indolizidines has been investigated. Only the indolizidines had significant activity, the nature of which depended upon the orientation of the phenyl substituent. The 2 alpha-phenyl isomers 5d-h were potent central dopamine D2 receptor antagonists with 5h showing selectivity for the limbic system. The 2 beta-phenyl isomer 5c was a gastric motility stimulant devoid of significant central dopamine receptor antagonist activity. Implications on receptor models are discussed.

The gastric prokinetic action of metoclopramide may not be primarily due to its dopamine antagonist activity. The present aim was to obtain a selective gastric prokinetic agent lacking dopamine antagonist activity by conformationally restricting the side chain of metoclopramide. In a series of quinolizidinylbenzamides, only compounds with the benzamide moiety at position 2 of the quinolizidine ring retain gastric activity. Of these 2-substituted compounds, the 2 alpha, 9a alpha isomer has potent selective gastric prokinetic activity with only weak dopamine antagonist properties. Spectroscopic data show that the quinolizidine ring preferentially adopts a trans chair-chair conformation with an axial benzamide moiety. However, energy calculations indicate that, at nondopaminergic receptors controlling gastric motility, an alternative cis chair-chair conformation with an equatorial benzamide moiety cannot be ruled out.

BRL 34778, exo-4-amino-5-chloro-2-methoxy-N-[9-(4-fluorophenylmethyl)-9-azabi cyclo(3.3.1) non-3-yl]-benzamide, is a very potent and specific dopamine D2-receptor antagonist. It exhibits a Ki value of 2.14 nM for dopamine D2-receptors but much lower affinity for D1-(Ki 5700 nM) and for many other receptor types. Its action is potent and of long duration in models for antipsychotic activity (4 h ED50s PO are 0.017 mg/kg for antagonism of apomorphine-induced climbing in mice and 0.028 mg/kg for antagonism of amphetamine-induced locomotion in rats). In contrast to its high potency in models for antipsychotic activity, BRL 34778 is much weaker in models for extrapyramidal effects and sedation (4 h ED50s PO are 2.4 mg/kg for inducing catalepsy in rats and 1.14 mg/kg for inhibition of rearing behaviour in rats). These data indicate potent activity of BRL 34778 in models for antipsychotic activity but low activity in models for extrapyramidal effects and sedation.