Maria J. Mokrosz

Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties

The effect of single and multiple 1‐methyl‐1,2,3,4‐tetrahydroisoquinoline (1MeTIQ) and 1‐benzyl‐1,2,3,4‐tetrahydroisoquinoline (1BnTIQ) administration on concentrations of dopamine and its metabolites: homovanillic acid (HVA) and 3,4‐dihydroxyphenylacetic acid (DOPAC) and 3‐methoxytyramine (3MT) in three brain areas was studied HPLC with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N‐oxidative and O‐methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. In addition, the spontaneous and apomorphine‐stimulated locomotor activity, and muscle rigidity was studied after acute administration of 1MeTIQ and 1BnTIQ. We have found that 1MeTIQ did not change the level of dopamine and HVA in all investigated structures both after a single and chronic administration. However, the levels of intermediary dopamine metabolites, DOPAC and 3MT, were distinctly affected. The level of DOPAC was strongly depressed (by 60–70%) while the level of extraneuronal matabolite 3MT was significantly elevated (by 170–200%). In contrast to 1MeTIQ, 1BnTIQ depressed the level of dopamine (by approximately 60%) and increased the level of total metabolite, HVA, (by 40%) especially in the striatum, but the levels of DOPAC and 3MT remained unchanged. The paper has shown that 1MeTIQ and 1BnTIQ produced different effects on dopamine catabolism. Potential neuroprotective compound 1MeTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the monoamine oxidase (MAO)‐dependent catabolic pathway and significantly activated the catechol‐O‐methyltransferase (COMT)‐dependent O‐methylation. In contrast 1BnTIQ, a compound with potential neurotoxic activity, produced the significant increase of the rate of dopamine metabolism with strong activation of the oxidative MAO‐dependent catabolic pathway. Interestingly, both compounds produced similar antidopaminergic functional effects: antagonism of apomorphine hyperactivity and induction of muscle rigidity. The results may explain the biochemical basis of the neuroprotective and of the neurotoxic properties endogenous brain tetrahydroisoquinoline derivatives.

Structure-activity relationship analysis of substituted 4-quinolinamines, antagonists of immunostimulatory CpG-oligodeoxynucleotides

On the basis of a systematic SAR analysis of substituted quinolines, a derivative 32 was synthesized that shows half-maximal inhibition of the immunostimulatory effect of CpG-oligodeoxynucleotides in vitro at the concentration of 0.24 nM.

Synthesis, 5-HT1A and 5-HT2A receptor affinity of new 1-phenylpiperazinylpropyl derivatives of purine-2,6- and pyrrolidine-2,5-diones

Two series of 1-phenylpiperazinylpropyl derivatives 10, 11, 16, 17 and 19-24, structurally related to previously described 5-HT1A or 5-HT2A ligands 4 and 1, respectively, were synthesized and their binding properties were determined. Structural modifications which involved 1,3-diazepine ring opening in 4 (compounds 10, 11, 15, 16) and replacement of spiroalkyl moiety in 1 by aryl substituent (19-24) did not improve binding affinity and selectivity of the tested compounds. The results showed, however, that the diazepine ring present in 4 or spiroalkyl ring in 1 are important for high 5-HT1A or 5-HT2A binding affinity and selectivity of these compounds.

1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands.

Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the terminal amide substituent was a crucial parameter which determined 5-HT1A receptor affinities of the tested compounds, while the in vivo activity seemed to depend on both the R-volume and the length of a hydrocarbon chain. It was demonstrated that the most active ligands behaved like agonists or partial agonists at postsynaptic 5-HT1A receptors.

Structure-activity relationship studies of CNS agents. Part 29. N-Methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel α1, 5-HT1A and 5-HT2A receptor ligands

Summary New N -methylpiperazino-substituted quinazolines 8 and 9 , phthalazine 13 , and quinoline 19 have been synthesized. The receptor binding profiles (α 1 , 5-HT 1A , 5-HT 2A ) of these compounds and their analogs ( 7–22 ) have been determined. It has been demonstrated that orientation of a local dipole moment of the heteroaromatic ring system affects both the α 1 and 5-HT 2A affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT 2A affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective α 1 ligand ( K i = 4.9 nM) with a much lower affinity for 5-HT 1A ( K i = 3420 nM) and 5-HT 2A ( K i = 211 nM) receptors.

Structure-activity relationship studies of CNS agents-XVII. Spiro[piperidine-4′,1-(1,2,3,4-tetrahydro-β-carboline)] as a probe defining the extended topographic model of 5-HT1A receptors

Abstract Spiro[piperidine-4′,1-(1,2,3,4-tetrahydro-β-carboline)] ( 10 ), its derivatives 11–15 and its analogs 16 and 17 were examined as ligands of serotonin 5-HT 1A receptors. It was shown that compounds 12 and 14 had essentially the same 5-HT 1A affinity as 1-phenylpiperazine and its rigid analog 7 , whereas there were substantial differences in the steric arrangement of their crucial pharmacophores, i.e. aromatic and protonation centers. On the basis of the existing models and using the (+)-LSD structure as a template, a new, extended three-point topographic model of 5-HT 1A receptors has been proposed.

Novel 1,4‐Benzoxazin‐3(4H)‐one, 1,2‐Benzoxazolin‐3‐one and 1,3‐Benzoxazolin‐2,4‐dione Arylpiperazine Derivatives with Different 5‐HT1A and Antagonistic 5‐HT2A Activities

New 1‐arylpiperazine (series d—f) and 1,2,3,4‐tetrahydroisoquinoline (series g) derivatives of 1,4‐benzoxazin‐3(4H)‐one 1, 1,2‐benzoxazolin‐ 3‐one 2, and 1,3‐benzoxazolin‐2,4‐dione 3 with an n‐butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5‐HT1A and 5‐HT2A receptors in comparison with trimethylene analogues (a, b c). 5‐HT1A receptor binding constants of derivatives 1d—g, 2d—f, and 3d—f were very high (Ki = 1.25—54 nM), and 5‐HT2A affinities were maintained at a similar, high level (Ki = 27—85 nM) for series d and e, and moderate (Ki = 246—495 nM) for series f. In respect of a spacer, the obtained results showed either no effect or a slight increase in the 5‐HT1A/5‐HT2A affinity in case of derivatives of 1 and 2, respectively. A striking effect was observed for derivatives 3d and 3f, whose 5‐HT1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5‐HT2A binding constants in comparison with trimethylene analogues. As shown by X‐ray crystallography, this phenomenon may be attributed to the position of non‐carbonyl oxygen atom in the amide moiety. In vivo studies demonstrated that compounds 1e—g, 2d—f, and 3f behaved like typical postsynaptic 5‐HT1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstrated 5‐HT2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5‐HT1A antagonist.

The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT1A/5-HT2A receptor activities of its 1-adamantoyloaminoalkyl derivatives

Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT(1A) ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT(1A) and 5-HT(2A) receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT(1A) receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT(1A) ligands (K(i)=4.9-46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT(1A) receptors. At the same time, their 5-HT(2A) receptor affinity was slightly increased (K(i)=40-1475 nM), which resulted in a loss of 5-HT(2A)/5-HT(1A) selectivity. 5-Br,8-OCH3 derivative-the most potent, mixed 5-HT(1A)/5-HT(2A) ligand-produced activation of presynaptic 5-HT(1A) receptors and showed properties of a 5-HT(2A) receptor antagonist.

Immunomodulating action and structure-activity relationships of substituted phenylamides of 5-amino-3-methylisoxazole-4-carboxylic acid.

A series of 5‐amino‐3‐methylisoxazole‐4‐carboxylic acid amides has been prepared by condensation of 5‐amino‐3‐methylisoxazole‐4‐carboxylic acid with ethyl chloroformate. The resulting mixed anhydride undergoes condensation with appropriate phenylamides to form the corresponding amides 6‐16. The compounds obtained were evaluated for their immunological activities in cultures of human peripheral blood mononuclear cells (PMBC). We found that the activities of the compounds in the proliferation test and in the lipopolysaccharide (LPS)‐induced cytokine production in PBMC cultures were differential. The stimulatory or inhibitory effects depended strongly on the origin and location of substituents in the phenyl ring which is described in the discussion and was supported by QSAR studies.

4-(3-furyl)-2-(4-methylpiperazino)pyrimidines: Potent 5-HT2A receptor antagonists

Abstract The title pyrimidines 7–12 are potent 5-HT2A receptor ligands with fairly strong behavioral antagonistic activity. A comparison of the structural and binding properties within the entire group of these and other pyrimidines demonstrates two different modes of the bioactive complex formation.