Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists

A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H(1) receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M(1)-M(5)) and for human histamine H(1) receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [(3)H]N-methylscopolamine ([(3)H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors ((S)-dimethindene: pK(i) = 7.52; (-)-19: pK(i) = 7.37) with an improved selectivity pattern ((S)-dimethindene: M(2)/M(1) = 6-fold, M(2)/M(3) = 5-fold, M(2)/M(4) = 10-fold, M(2)/M(5) = 25-fold; (-)-19: M(2)/M(1) = 36-fold, M(2)/M(3) = 96-fold, M(2)/M(4) = 42-fold, M(2)/M(5) = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H(1) receptors (pK(i) = 5.61) than (S)-dimethindene (pK(i) = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pK(i)/M(2) = 7.49), which also exhibits a higher M(2) selectivity (M(2)/M(1) = 19-fold; M(2)/M(3) = 22-fold; M(2)/M(4) = 13-fold; M(2)/M(5) = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H(1) receptors (pK(i) = 8.14). The compound with the highest affinity for M(2) receptors (pK(i) = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M(2) receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M(2) receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M(2)-selective muscarinic antagonists useful for quantifying M(2) receptors in the central nervous system with positron emission tomography imaging.     

The effect of allosteric antagonists in modulating muscarinic M2-receptor function in guinea-pig isolated trachea.

1. We have assessed the influence of a range of synthetic cationic polypeptides with putative inhibitory actions at prejunctional muscarinic M2-receptors on electrical field stimulation-induced contraction of guinea-pig isolated tracheal preparations. Electrical field stimulation of epithelium-denuded guinea-pig trachea resulted in frequency-dependent contractile responses. As expected, tracheal smooth muscle sensitivity to electrical field stimulation was increased in tissues pretreated with the muscarinic M2-receptor antagonist, gallamine. In contrast, gallamine did not significantly alter the contractile potency to acetylcholine. 2. Unlike gallamine, the synthetic cationic polypeptides, poly-L-arginine, poly-L-lysine, poly-D-lysine, the cationic dye ruthenium red and the anionic polysaccharide, heparin, failed to increase significantly tracheal smooth muscle sensitivity to electrical field stimulation. 3. Poly-L-arginine, ruthenium red and heparin had no effect on the contractile response to exogenously applied methacholine. 4. These data are consistent with the concept that in guinea-pig tracheal smooth muscle, gallamine is an allosteric antagonist of guinea-pig tracheal muscarinic M2-receptors, whereas the various cationic polypeptides and the polyanion, heparin, are not.     

Structure-activity relationships in the acronycine series

Acronycine is active against a broad spectrum of solid tumors. Structure activity relationships demonstrated the crucial role of the 1,2-double bond. A hypothesis of bioactivation into 1,2-epoxide led to the development of a series of 1,2-dihydroxy-1,2-dihydroacronycine and 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diesters that exhibited an increased potency when compared with the parent compound.     

Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics

On the basis of the cardioselective muscarinic receptor antagonist AF-DX 116 (2), a series of 11-substituted pyridobenzodiazepinones (9-35) was prepared and screened for their binding affinity to muscarinic receptors located in cardiac (M2) and glandular (M3) tissue. The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of cardiac (M2) receptor selectivity. Qualitative structure-selectivity relationships point to the fact that it is the spatial orientation of the protonated side-chain nitrogen atom in relation to the tricycle that is the main determinant for receptor subtype recognition and hence is important for the achievement of cardiac (M2) selectivity.     

Structure-activity relationships for a series of phenylglycine derivatives acting at metabotropic glutamate receptors (mGluRs).

1. The actions of a series of twelve phenylglycine derivatives at metabotropic glutamate receptors (mGluRs) linked to both phosphoinositide hydrolysis (PI) and cyclic AMP were investigated. 2. PI hydrolysis was determined by the accumulation of [3H]-inositol-monophosphate ([3H]-IP1) in neonatal ral cortical slices prelabelled with [3H]-myo-inositol. The non-selective mGluR agonist (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S,3R)-ACPD) produced a concentration-dependent increase in [3H]-IP1 (EC50 approximately 20 microM). This agonist was subsequently used to investigate potential antagonist activity of the phenylglycine derivatives. Of the compounds tested (+)-alpha-methyl-4-carboxyphenylglycine (M4CPG) and (RS)-alpha-ethyl-4-carboxyphenylglycine (E4CPG) were the most active with KP values of 0.184 +/- 0.04 mM and 0.367 +/- 0.2 mM respectively. 3. Activity at adenylyl cylase-coupled mGluRs was investigated by determining the accumulation of [3H]-cyclic AMP in adult rat cortical slices. [3H]-cyclic AMP accumulation, elicited by 30 microM forskolin, was inhibited by (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-1) and L-2-amino-4-phosphonobutanoate (L-AP4) with respective EC50 values of 0.3 microM and 10 microM. Neither agonist was able to inhibit completely forskolin stimulated cyclic AMP accumulation; this is evidence that not all adenylyl cyclase is susceptible to modulation by mGluRs. Phenylglycine derivatives were examined for their ability to antagonize the inhibition of [3H]-cyclic AMP accumulation by L-CCG-1 or L-AP4 at their EC50 concentrations. 4. A rank order of potency of the phenylglycine derivatives as antagonists of L-AP4 and L-CCG-1 was obtained. The most effective compound. (RS)-alpha-methyl-3-carboxymethylphenylglycine (M3CMPG) had IC50 values in the order of 1 microM against L-AP4 and 0.4 microM against L-CCG-1. 5. The results from this study indicate that phenylglycine-derived compounds can discriminate between groups of metabotropic glutamate receptors and may also display some selective activity between subtypes within groups. Future work based on these findings may lead to the development of more selective and potent compounds as important pharmacological tools.     

Structure-activity relationships of new analogues of arecaidine propargyl ester at muscarinic M1 and M2 receptor subtypes.

1. The potency of arecaidine propargyl ester (APE) and of several analogues containing a modified ester side chain has been assessed at M1 and M2 muscarinic receptor subtypes. APE was shown to act as a potent agonist at ganglionic M1 receptors in the pithed rat, at M2 receptors in guinea-pig isolated atria (-log EC50 = 8.22) and ileum (-log EC50 = 7.77). 2. The arecaidine 2-butynyl and 2-pentynyl esters were approximately equipotent with APE at M1 and M2 receptors, whereas the 2-hexynyl derivative was found to be less potent than APE in atria (-log EC50 = 6.80) and ileum (-log EC50 = 6.70) by about one order of magnitude. The 2-heptynyl and 3-phenyl propargyl esters exhibited no agonist actions in atria and ileum. 3. Shifting the triple bond from the 2 to the 3 position and introducing a bulky group at position 1 of the ester side chain of APE and analogues resulted in competitive antagonists (pA2 ranging from 4.9 to 7.3). 4. APE and its 2-butynyl analogue showed some agonistic selectivity for cardiac M2 receptors (potency ratio, ileum/atria = 2.8 and 4.6 respectively). All antagonists in this series of compounds were not selective in terms of affinity since their pA2 values at cardiac and ileal M2 receptors were similar (potency ratios, ileum/atria = 0.4 to 1.2).     

Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives

A series of analogues of buspirone was synthesized in which modifications were made in the aryl moiety, alkylene chain length, and cyclic imide portion of the molecule. These compounds were tested in vitro for their binding affinities to rat brain membrane sites labeled by either the dopamine antagonist [3H]spiperone or the alpha 1-adrenergic antagonist [3H]WB-4101. Compounds were also tested in vivo for tranquilizing properties and induction of catalepsy. Potency at the [3H]spiperone binding site was affected by alkylene chain length and imide portion composition. Nonortho substituents on the aryl moiety had little effect on [3H]spiperone binding affinity. Structure-activity relationships of ortho substituents demonstrated only modest correlations between the receptor binding data and physical parameters of the substituents. The complex nature of the drug-receptor interactions may be understood in terms of the fit of buspirone to a hypothetical model of the dopamine receptor.     

Structure-activity relationships in the series of eremomycin carboxamides

A series of new carboxamides of the glycopeptide antibiotic eremomycin was synthesized and investigated in vitro. The goal of the study was the comparison of the influence of the substituents introduced onto the eremomycin skeleton on the activity of these compounds against vancomycin susceptible and resistant bacterial strains. Eremomycin amides derived from amines with small substituents (C0 approximately C4) demonstrated antibacterial activity against vancomycin susceptible strains similar to that of the parent antibiotic and were inactive against vancomycin resistant strains. The derivatives of alkylamines with linear lipophilic substituents (like C10H21) were active against VanA and VanB enterococci strains with the scope of activity similar to that of N'-decyl or 7d-CH2NH-decyl eremomycins described earlier. Eremomycin amides of 5-methoxy- and 5-benzyloxytryptamine were active both against vancomycin susceptible and resistant strains. The introduction of a spacer (lysine or piperazine) between the decyl and antibiotic moieties did not seriously influence antibacterial properties of the compounds in comparison with the corresponding derivatives without a spacer. The most active carboxamides are of interest for secondary modifications of the antibiotic.     

Piperidinediones, III. Structure-activity relationships of the enantiomers of a series of 2,6-piperidinedione derivatives

Among the racemic 2,6-piperidinediones 1 – 6 , compound 6 has the highest anesthetic activity. The enantiomers of 1, 2, 4 and 5 possess different anesthetic potencies depending on the nature of the aliphatic side chain. The S(-)-enantiomers of the piperidinediones 2, 3 and 5 cause initial CNS stimulation with convulsive symptoms followed by anesthesia.     

H2-antihistaminics. 20. Structure-activity relationships in H2-receptor antagonists containing a 4-pyrimidone moiety

In a series of 5,6-substituted 4- pyrimidones 1 a-v the H2-antihistaminic activity was determined (guinea-pig atrium) and lipophilicity data are given in form of Rmo -values. The influence of different substituents at position 5 or 6 of a pyrimidone moiety has been studied. Quantitative structure-activity analyses showed the importance of lipophilicity for drug activity. Additionally other physicochemical substituent-properties may play a major role.     

Structure-activity relationships in the 2-arylcarbapenem series: synthesis of 1-methyl-2-arylcarbapenems

The labile tert-butyldimethylsilyl esters of the azetidinones 6-8b served as the crucial synthons in the preparation of the potentially useful ylide pyridyl thio esters 18-20. These intermediates were utilized to synthesize a host of title carbapenems 25-30d, 32, and 49-53. The antimicrobial properties and DHP-I susceptibility of these carbapenems were studied with reference to thienamycin.     

Structure-activity relationships (SAR) of the 3-alkyl substituents among a series of hydroxy-acetophenone leukotriene antagonists

LY171883 is an orally active antagonist of leukotriene (LT) D4 and LTE4. A series of related compounds varying the position and nature of the alkyl side chain were synthesized and evaluated for their ability to block LTD4-induced contraction of guinea pig ileum. Maximal activity was obtained with n-propyl, n-butyl, and n-pentyl substituents with slightly reduced activity for longer side chains. Polar groups on the side chain substantially reduced activity. Thus, it appears that the leukotriene receptor site requires a nonpolar alkyl group of moderate size at the 3-position on this type of receptor antagonist.     

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.     

Structure-activity relationships in some series of 2-alkyl-1,2,3,-benzotriazinium compounds

1. The potencies of four series of N-alkyl-1,2,3-benzotriazinium iodides have been estimated on the frog rectus abdominis and chick biventer cervicis preparations.2. The partition coefficients between chloroform and water were measured for all of the compounds, as well as the ionization constants for some members of two of the series.3. The potencies of the compounds increased with the number of carbon atoms in the N-alkyl side chain up to a maximum at the n-butyl homologue while partition coefficients increased up to the n-pentyl homologue, and there may be some association between the lipid solubilities of the compounds and their biological activity.4. The responses of the tissues to the benzotriaziniums were not abolished by tubocurarine, indicating that the site of action was not at acetylcholine receptors.5. The similarity between the actions of the benzotriaziniums and those of quinine and quinidine is discussed.     

Structure-activity relationships of phencyclidine derivatives in rat cerebellum

The depressant effects of phencyclidine [1-(1-phenylcyclohexyl) piperidine, PCP] and three of its analogs (m-amino-PCP, m-nitro-PCP, and PCP-methyliodide) on the spontaneous action potential discharge of cerebellar Purkinje neurons in urethane-anesthetized rats were examined in this study. Both intraperitoneal injection and micro-pressure ejection were employed as routes of drug administration. The relative potency after parenteral administration corresponded closely with previous findings in behavioral test paradigms. PCP and m-amino-PCP were equipotent, m-nitro PCP was less potent than either PCP or m-amino-PCP, and PCP-methyliodide showed almost no activity. After local administration onto neurons, m-amino-PCP was significantly more potent than PCP, while PCP, m-nitro-PCP, and PCP-methyliodide were equipotent. Tritiated PCP, m-nitro PCP, and m-amino PCP have similar distribution and metabolism in cerebellum. PCP-methyliodide, a quaternary ion, does not cross the blood brain barrier. M-nitro PCP is appreciably less ionized at pH 7.4 than PCP or m-amino-PCP and, therefore, may be more easily sequestered into lipids. Differences between PCP and its analogs found in experiments which employ parenteral administration may reflect differences in drug distribution. These differences are minimized when these drugs are administered directly onto neurons via pressure microejection.     

Probing the pharmacophore for allosteric ligands of muscarinic M2 receptors: SAR and QSAR studies in a series of bisquaternary salts of caracurine V and related ring systems

Allosteric effects on muscarinic acetylcholine M(2) receptors were examined in a series of bisquaternary salts of the Strychnos alkaloid caracurine V (6) and related iso-caracurine V, tetrahydrocaracurine V, and bisnortoxiferine ring systems. The compounds inhibited dissociation of the orthosteric antagonist [(3)H]N-methylscopolamine (NMS) from porcine cardiac M(2) receptors with EC(0.5,diss) values from 4 to 3270 nM. The majority of compounds hardly changed [(3)H]NMS equilibrium binding, indicating similar binding affinities in free and NMS-occupied M(2) receptors. The most potent agents were found in the caracurine V, iso-caracurine V, and tetrahydrocaracurine V series and carried nonpolar alkyl groups with a maximal chain length of three carbon atoms. 3D QSAR (CoMSIA) analysis explained the wide range of binding affinities by steric and electrostatic properties of the side chains. Furthermore, the findings suggest that the spatial orientation of the "caracurine" aromatic rings compared with the bisnortoxiferine ring skeleton is favorable to optimal allostere-receptor interactions.     

Buspirone analogues. 2. Structure-activity relationships of aromatic imide derivatives

Several analogues of the novel anxiolytic buspirone were synthesized and evaluated in vivo for tranquilizing activity and their ability to reverse neuroleptic-induced catalepsy. The in vitro binding affinities of these compounds were also examined for both the alpha 1 and dopamine D2 receptor systems. The general structure-activity relationships of this series highlight compounds 17, 21, and 32 as having anticonflict activity. Each of these structures contains the 1-(2-pyrimidinyl)piperazine moiety linked by a tetramethylene chain to a variable cyclic imide moiety. Compound 32 (4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6- piperidinedione) was found to be equipotent with buspirone in its anxiolytic activity and was therefore selected for extensive preclinical characterization. The pharmacology of buspirone and 32 is contrasted, and the potent serotonin agonist properties of 32 are discussed with reference to its potential contribution to the anxioselective mechanism of this compound.