Synthesis of novel 5-substituted 3-amino-3,4-dihydro-2H-1-benzopyran derivatives and their interactions with the 5-HT1A receptor.

A series of new enantiomerically pure 3-amino-3,4-dihydro-2H-1-benzopyrans (3-aminochromans) has been synthesized from (R)- and (S)-5-methoxy-3-amino-3,4-dihydro-2H-1-benzopyran. The absolute configuration of the respective (R)- and (S)-enantiomers was deduced from X-ray crystallography of (R)-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran, (R)-9a. Various 5-substituents were introduced via palladium-catalyzed carbonylation of N-substituted 3-amino-5-trifluoromethanesulfonyloxy-3,4-dihydro-2H-1-benzopyran. The effect of N- and 5-substitution on affinity for the 5-HT1A receptor was evaluated in competition experiments using rat hippocampal membranes and [3H]8-OH-DPAT as radioligand. Selected compounds were also tested for their affinity to the D1 (rat striatum), D2 (rat striatum), D2A (human cloned), and 5-HT2A (rat cortex) receptors. The intrinsic activity of the compounds was evaluated by measuring their effect on VIP-stimulated cAMP production in GH4ZD10 cells stably transfected with the 5-HT1A receptor. High-affinity compounds with high selectivity for the 5-HT1A receptor were found among structures substituted with carboxylate esters, amides, and ketones in the 5-position. Primary and secondary amines bound with lower affinity than tertiary amines. Larger substituents were well-tolerated by the receptor, but the smaller N-ethyl-N-isopropyl bound with lower affinity. Generally, the (R)-enantiomers displayed higher affinity for the 5-HT1A receptor than the corresponding (S)-enantiomers. In the present series of compounds, both full and partial agonists were found.

Synthesis and pharmacology of the enantiomers of UH301: opposing interactions with 5-HT1A receptors.

The (S)-enantiomer of 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin [(S)-2a; (S)-UH301] was the first reported 5-HT1A receptor antagonist. We now give a full account on the synthetic effort leading to the preparation of the racemate and the enantiomers of 2a. The crystal and molecular structure of 2a. HBr has been determined by X-ray diffraction and the absolute configuration has been deduced using statistical tests of the crystallographic R values. The unit cell is tetragonal (P4(1)2(1)2) with a = b = 13.2235(2), c = 39.560(1) A and contains two crystallographically independent molecules in each asymmetric unit. The two solid state conformers differ in the conformation of the N-propyl groups. The pharmacological characterization of the enantiomers was done by use of in vivo biochemical and behavioural assays in rats. The (R)-enantiomer of 2a is a 5-HT1A receptor agonist of low potency while (S)-2a does not exhibit any agonist properties at 5-HT1A receptors. As a consequence of the opposing effects of the enantiomers, the racemate, rac-2a, does not produce any clear-cut effects in rats. The reduced efficacy of (S)-2a as compared to the well known 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino) tetralin (1;8-OH-DPAT) may be due to the fluoro-substituent induced negative potential of the aromatic ring.

Enhanced stereoselectivity in pig liver esterase catalysed diester hydrolysis. The role of a competitive nucleophile.

The enantioselectivity of pig liver esterase catalysed hydrolysis of cis-N-benzyl-2,5-bis(methoxy-carbonyl)pyrrolidine (1) has previously been shown to be very dependent on the reaction conditions. Hydrolysis performed in media buffered with tris(hydroxymethyl)aminomethane (Tris) afforded a monoester with much higher optical purity than hydrolysis in media without Tris. Detailed product studies in a Tris-buffered medium have been performed using NMR-techniques and a 13C-labelled ester. The NMR-studies revealed the presence of (2S,5R)-N-benzyl-2-methoxycarbonyl-5-[[[2-hydroxy-1,1- bis(hydroxymethyl)ethyl]amino]carbonyl]pyrrolidine (4) as an intermediate, which together with the isolated product (2S,5R)-N-benzyl-2-carboxy-5-[[[2-hydroxy-1,1-bis(hydroxymethyl) ethyl]amino]carbonyl]pyrrolidine (3) suggested Tris as a competitive nucleophile to water. The increased enantioselectivity seen in the produced (2R,5S)-N-benzyl-2-methoxy-carbonyl-5-carboxypyrrolidine (2) was explained by the preference of Tris to react faster with one of the diastereomeric acyl enzymes over the other.

Molecular and crystal structure of the hydrochloride monohydrate of (R)-N-[[1-(4-fluorobenzyl)-2-pyrrolidinyl]methyl]-5-bromo-2,3- dimethoxybenzamide, NCQ 115, a novel dopamine D2 receptor antagonist.

The structure and absolute configuration of the title compound have been determined by single crystal X-ray diffraction analysis. The space group symmetry is R21; the monoclinic unit cell contains two molecules and has the dimensions a = 12.4291(8), b = 7.4511(5), c = 12.7854(7) angstroms and beta = 102.295(7) degrees. The planar conformation of the benzamide moiety is stabilized by an intramolecular (N)H...O bond. Hydrogen bonds connect the chloride anion to the protonated pyrrolidine N atom, and also the crystal water to the carbonyl oxygen of the amide group. The molecule has a folded conformation in which the N-fluorobenzyl substituent of the pyrrolidine ring and the H-bonded pseudo ring of the benzamide moiety are arranged in a sandwich-like manner. In the crystal, intermolecular hydrogen bonds link the drug molecules via the chloride anion and the hydrate molecule into endless helical chains around the twofold axis. The absolute configuration was determined by comparison of the wRtot values, 0.037 and 0.040, calculated using all measured 2027 unique, non-zero reflections and assuming R and S configuration for the chiral center, respectively. Refinement of the structural model with an R configuration resulted in the final indices of R = 0.031 and wR = 0.033 for 1512 reflections with I/delta(I) greater than 3.

Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides. Relations to other side chain congeners.

A number of substituted N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides and -salicylamides have been prepared and investigated as dopamine D-2 receptor antagonists in vitro and in vivo. The affinity was found to be confined to the R enantiomer, in contrast to the corresponding N-ethyl or N-allyl derivatives. The X-ray structure of one of the compounds (15) confirmed the R stereochemistry. This compound (15) was found to adopt a solid-state conformation in which the 4-fluorobenzyl group is folded over the salicylamide moiety. Benzamides having a 2,3-dimethoxy substitution pattern (24 and 26) or salicylamides with a 5,6-dimethoxy grouping (21 and 22) were especially potent, in that they inhibited [3H]spiperone binding to rat striatal dopamine D-2 receptors in vitro with IC50 values of about 1 nM. The new compounds' ability to block apomorphine-induced stereotypies correlated with the affinity for the [3H]spiperone binding site. Higher dose levels were necessary to induce catalepsy than to block the apomorphine-induced responses. The influence of the aromatic substituents on the potency of substituted benzamides with three types of side chains, i.e. (R)-(1-benzyl-2-pyrrolidinyl)methyl, (S)-(1-ethyl-2-pyrrolidinyl)methyl and 1-benzyl-4-piperidinyl, was compared. The 3-bromo-5,6-dimethoxysalicylamide substitution pattern was found to be the most general since it gave very potent compounds in all series. The substituted (R)-N-[(1-(4-fluoro-benzyl)-2-pyrrolidinyl)methyl]benzamides (26) and -salicylamides (22) are suitable for development into 18F radioligands without altering the parent structure.

A 3-D model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogues of 8-hydroxy-2-(dipropylamino)tetralin.

The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.

(R)- and (S)-5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten- 8-ylamine. Stereoselective interactions with 5-HT1A receptors in the brain.

The enantiomers of 5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-++ +ylamine (3) have been synthesized and evaluated for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor activity by use of behavioral and biochemical tests in rats. In addition, the ability of the compounds to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The absolute configuration of the enantiomers of 3 was determined indirectly by X-ray diffraction of (+)-(8R,alpha R)-5,6,7,8-tetrahydro-1-methoxy-N-(alpha-phenethyl)-9H- benzocyclohepten-8-ylamine hydrochloride (9.HCl), a resolved synthetic precursor. The stereoselectivity of the interaction of 3 with 5-HT1A receptors was more pronounced than that of 8-hydroxy-2-(dipropylamino)tetralin (1; 8-OH-DPAT); only (R)-3 displayed 5-HT activity. However, (R)-3 was of lower potency than any of the enantiomers of 1. The enantiomer (S)-3, which was found to be inactive as a 5-HT-receptor agonist, appeared to be a weakly potent DA-receptor agonist whereas (R)-3 seemed to be devoid of dopaminergic activity. The conformational preferences of 3 were studied by use of NMR spectroscopy and molecular mechanics calculations. Preferred conformations of (R)-3 are similar in shape to those of the stereoselective 5-HT1A-receptor agonist (2R,3S)-8-hydroxy-3-methyl-2-(dipropylamino)tetralin.

Structural analysis of two 2-deoxy analogues of alpha- and beta-KDO and the methyl alpha- and beta-glycosides of KDO, and determination of their metal-ion-binding properties.

Ammonium 2,6-anhydro-3-deoxy-D-glycero-D-talo-octonate (1), a potent inhibitor of the enzyme CMP-KDO synthetase, its C-2 epimer 2, and the methyl beta- (3) and alpha-glycoside (4) of KDO were studied by 1H- and 13C-n.m.r. spectroscopy. Compound 1 was also analysed by X-ray crystallography. Each compound adopted a 5C2 chair conformation with the side chain equatorial. The preponderant side-chain conformation of 1 in solution was the same as that in the crystal and was stabilised by an intramolecular hydrogen bond from HO-8 to the carboxylate group. This hydrogen bond appeared to be present also in 3. However, the side-chain conformation of 2 and 4 was different from that in 1 and 3. The metal-ion-binding properties, determined on the basis of the line-broadening effects of Mn2+ on the 13C-n.m.r. signals, showed that the carboxylate group was involved in the binding with O-8 in 1 and 3 and with O-6 and O-8 in 2 and 4.

Solid state conformations and antidopaminergic effects of remoxipride hydrochloride and a closely related salicylamide, FLA 797, in relation to dopamine receptor models.

The X-ray structures of two new 2,6-disubstituted benzamides, i.e., remoxipride hydrochloride monohydrate [-)-(S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenza mide hydrochloride monohydrate) and FLA 797 [-)-(S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamide ), have been determined as well as the distribution coefficients. The difference in dopamine receptor blocking activity is discussed in terms of lipophilicity and solid state conformations of the two benzamides. The major difference between the solid state conformations lies in the orientation of the carboxamide moiety. In remoxipride the carbonyl group is oriented almost perpendicularly to the benzene ring, thus preventing the formation of a hydrogen-bonded pseudo-ring between the amide hydrogen and the methoxy group found in other types of o-methoxybenzamides. In FLA 797, however, this pseudo-ring is present in the planar conformation of the salicylamide moiety. This conformation is further stabilized by a hydrogen bond between the phenol group and the carbonyl oxygen. The side chain in remoxipride adopts an extended conformation in contrast to FLA 797, where the side chain has a folded conformation. The crystal structures are related to current topographic dopamine receptor models developed from more rigid antidopaminergic compounds. Based on these comparisons, it is suggested that benzamides having an N-ethyl-2-pyrrolidinylmethyl side chain interact with the receptor in the folded conformation. The binding affinity is thought to be further increased by the planar conformation of the salicylamide moiety present in FLA 797, which permits an efficient pi-pi stacking interaction.