LE 300

Dopamine/serotonin receptor ligands. Part 15: Oxygenation of the benz-indolo-azecine LE 300 leads to novel subnanomolar dopamine D1/D5 antagonists.[Pubmed:17188870]

Bioorg Med Chem Lett. 2007 Mar 1;17(5):1399-402.

Relying on the high affinities of the benz-indolo-azecine LE 300 (1) and the hydroxylated dibenz-azecine LE 404 (2b) for the D1/D5 receptor subtypes, we synthesized methoxylated, hydroxylated and an indole-N methylated derivatives of 1 (Fig. 1). Hydroxylation of azecine derivatives is beneficial with regard to the affinities and selectivities for all the dopamine receptor subtypes. The 'serotonin-derived' 3-oxygenated target compounds but not the 11-oxygenated analogues were superior to the unsubstituted LE 300. 11-Methoxy-7,14-dimethyl-6,7,8,9,14,15-hexahydro-5H-indolo[3,2-f][3]benzazecine (3e) was found to be the most potent antagonist at D2/D3/D4 and D5 receptor subtypes (Ki for D5 = 0.23 nmol) of all known benz-indolo-azecines.

Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300.[Pubmed:11512275]

Arch Pharm (Weinheim). 2001 Jul;334(7):241-7.

An indolo[3,2-d]pyrrolo[3,2-g]azecine and a benzo[d]pyrrolo[3,2-g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine) have been prepared in multi-step reactions via C-N bond cleavage of corresponding quaternary N-methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5-HT2A receptors (rat tail artery) and H1 receptors (guinea-pig ileum), respectively. LE 300 and compound 19 (3,6-dimethyl-4,5,6,7,8,13-hexahydro-3H-benzo[d]pyrrolo[3,2-g]azecine) competitively inhibited 5-HT-induced contractions with similar nanomolar potency (pA2 = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA2 = 9.55). Compound 19 displayed moderate H1-antihistaminic activity in the guinea-pig ileum assay (pA2 = 7.37).

Spectrofluorimetric determination of dopamine receptor antagonist LE 300 in mice plasma.[Pubmed:25892547]

Luminescence. 2016 Feb;31(1):63-6.

A simple, rapid and highly sensitive spectrofluorimetric method was developed for determination of a novel type of dopamine receptor antagonist LE300 in mouse plasma. The method is based on measuring the native fluorescence of LE-300 in methanol at 343 nm after excitation at 280 nm. The fluorescence concentration plot was rectilinear over the range of 3.5-100 ng/mL with a lower detection limit of 1.0 ng/mL and quantification limit of 3.5 ng/mL. The method was statistically validated for linearity, accuracy, precision and selectivity according to the International Conference on Harmonization guidelines. The accuracy and precision results was expressed as % recovery and relative standard deviation (RSD). The accuracy for LE-300 was in the range 95.5-103.6% and RSD values were in the range of 0.21-1.55% of the theoretical value. The method was successfully applied to the analysis of LE-300 in mice plasma. The results were compared statistically with those obtained by the reported method and were found to be in good agreement, which could be applied in a pharmacokinetic study.

Novel fused pyrrole heterocyclic ring systems as structure analogs of LE 300: Synthesis and pharmacological evaluation as serotonin 5-HT(2A), dopamine and histamine H(1) receptor ligands.[Pubmed:20108267]

Arch Pharm (Weinheim). 2010 Feb;343(2):73-80.

LE 300 represents a structurally novel type of antagonists acting preferentially at the dopamine D(1)/D(5 )receptors and the serotonin 5-HT(2A )receptor. This compound consists of a ten-membered central azecine ring fused to an indole ring on one side and a benzene moiety on the other side. To estimate the importance of the indole and / or phenyl moieties in this highly active benz-indolo-azecine, both rings were removed and replaced with a 1H-pyrrole counterpart. Accordingly, some new analogs of LE 300 namely, pyrrolo[2,3-g]indolizine, pyrrolo[3,2-a]quinolizine rings and their corresponding dimethylpyrrolo[2,3-d]azonine, and dimethylpyrrolo[2,3-d]azecine were synthesized to be evaluated for their activity at the 5-HT(2A) and dopamine D(1), D(2L), D(4), D(5) receptors in relation to LE 300. In addition, their activity at the H(1)-histamine receptors was also determined. The results suggested that the rigid pyrrolo[2,3-g]indolizine 7 and pyrrolo[3,2-a]quinolizine 8 analogs lacked biological activity in the adopted three bioassays. However, their corresponding flexible pyrrolo[2,3-d]azonine 11 and pyrrolo[2,3-d]azecine 12 derivatives revealed weak partial agonistic activity and weak antagonistic potency at the serotonin 5-HT(2A )and histamine H(1 )receptors, respectively. Meanwhile, they showed no affinity to any of the four utilized dopamine receptors. Variation in ring size did not contribute to a significant influence on the three tested bioactivities. Removal of the hydrophobic moiety (phenyl ring) and replacement of the indole moiety with a 1H-pyrrole counterpart led to a dramatic alteration in the profile of activity of such azecine-type compounds.

Dopamine/serotonin receptor ligands. Part IV [1]: synthesis and pharmacology of novel 3-benzazecines and 3-benzazonines as potential 5-HT2A and dopamine receptor ligands.[Pubmed:12447918]

Arch Pharm (Weinheim). 2002 Nov;335(9):443-8.

LE 300 represents a structurally novel type of antagonist acting preferentially at the dopamine D1/D5 receptors and the serotonin 5-HT2A receptor. The compound consists of a 10-membered central azecine ring fused to indole on one and to benzene on the other side. To estimate the importance of the indole moiety in this highly active benz-indolo-azepine, the indole has to be removed and the "de-indolised" analog reinvestigated pharmacologically. Accordingly, we synthesized 3-benzazecines and in addition some homologuous 3-benzazonines. Methoxylated beta-phenylethylamines were treated with ethyl omega-bromo-butanoates and -pentanoates, respectively, to give the corresponding lactams which were cyclized (POCl3) and reduced (NaBH4), yielding the cis-annelated (X-ray) benzindolizines and -quinolizines. The 10- and 9-membered rings were obtained by cleavage of the central C-N bond, which was performed in the following two ways: Quarternisaion with methyl iodide and cleavage with sodium in liquid ammonia gave the NCH3 derivatives, reaction with benzyloxycarbonyl chloride/NaBH4 followed by catalytic debenzylation yielded a corresponding NH compound. Functional experiments on rat artery segments precontracted with ketanserin and radioligand binding experiments using human cloned dopamine receptor subtypes were conducted with all of the benzazecine and benzazonine derivatives. In contrast to the benz-indolo-compound LE 300 they did not show any significant affinity towards the D1, D2, D4, and D5 receptors and only moderate antagonistic activity at the 5-HT2A receptor. It can be concluded from our study that an indole moiety or at least another second aromatic system at the central azecine ring is part of the pharmacophore and thus essential for high biological activity.

Pharmacological characterization of the benz[d]indolo[2,3-g]azecine LE300, a novel type of a nanomolar dopamine receptor antagonist.[Pubmed:12444495]

Naunyn Schmiedebergs Arch Pharmacol. 2002 Dec;366(6):543-50.

LE300 (7-methyl-6,7,8,9,14,15-hexahydro-5 H-benz[d]indolo[2,3-g]azecine), a previously reported subnanomolar antagonist at rat striatal dopamine D1 receptors, and three of its azecine-N-substituted congeners combining structural elements of serotonin and dopamine were comprehensively characterised (binding and function) at recombinant human dopamine receptors. Radioligand competition experiments at D1 and D2L receptors were performed by using [(3)H]SCH23390 and [(3)H]spiperone, respectively. Functional assays included measurements of cAMP, intracellular [Ca(2+)], and [(35)S]GTPgammaS-binding. LE300 was the most potent compound with a 10- to 20-fold selectivity for D1 over D2L receptors as measured in equilibrium binding experiments [competition radioligand binding: K(i)(D1)=1.9 nM, K(i)(D2L)=44.7 nM; [(35)S]GTPgammaS-binding: K(i)(D1)=1.8 nM, K(i)(D2L)=21.5 nM]. In functional (non-equilibrium) experiments, LE300 did not reveal a D1 over D2L selectivity but retained nanomolar K(i) values at human dopamine receptors (measurement of cAMP: K(i)(D1)=25.9 nM, K(i)(D2L)=5.2 nM; measurement of intracellular [Ca(2+)]: K(i)(D1)=60.4 nM, K(i)(D2L)=19.0 nM). LE300 is currently under investigation for usefulness as positrone emission tomography ligand. In conclusion, LE300 is a novel type of a nanomolar dopamine receptor antagonist combining structural core elements of dopamine and serotonin, and may become useful as positrone emission tomography ligand.

7-Methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine: a new heterocyclic system and a new lead compound for dopamine receptor antagonists.[Pubmed:10821720]

J Med Chem. 2000 May 18;43(10):2079-81.

Partially hydrogenated derivatives of the new heterocyclic ring systems benz[d]indolo[2,3-g]azecine and bisindolo[3,2-d][2, 3-g]azecine were synthesized starting from lactones and amines via the described synthetic methods. In binding assays with rat striatal receptors, 7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2, 3-g]azecine (LE 300) proved to be of high affinity for the D(1) binding site (K(i) = 0.08 nmol for displacement of [(3)H]SCH23390), being superior in this assay to standards such as butaclamol and SCH23390. This compound was characterized as a dopamine antagonist by conditioned avoidance response test with mice. Thus, LE 300 represents the lead of a new class of dopamine antagonists for future investigations.