Abstract

Nitrogen-bound diazen-1-ium-1,2-diolates (diazeniumdiolates, “NONOates”, “solid NO”) are generally prepared from secondary amines and nitric oxide and are compounds of first choice for the direct release of nitric oxide (NO). First, we report on the relationships between the structures of the amines and the formation rates of the corresponding NONOates, second on the structures of the NONOates and the rate of NO release and finally between the rates of NONOate formation and NO release from these species. A series of differently sized and substituted cyclic and aliphatic amines were used to quantify the reactivity of amines towards NO by monitoring the decrease in NO pressure with the NOtizer, an apparatus developed for this study. The release of NO was measured amperometrically with an NO-sensitive electrode and the half-lives of novel diazeniumdiolates were determined by UV spectroscopy. It was found that steric hindrance and heteroatomic substituents in the amines' side chains reduce the formation rates of the sodium salts of the NONOates and also slow down NO release from them. Exceptions were found with piperidine-2-carboxylic acid derivatives which react to give NONOates more slowly than piperidine but release NO much faster despite steric hindrance. A secondary amine carrying an additional primary amine reacted quickly with NO, but the corresponding NONOate showed slower releaser of NO owing to the formation of an intramolecular NONOate salt as well as the sodium salt derivative. Azetidine reacts faster with NO than all of the other amines, but decomposition of the corresponding NONOate proved to be unexpectedly slow.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A number of 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles 3 were synthesized with different substituents at the azepine-N position (methyl-, allyl-, 2-phenyl-ethyl-, cyclopropylmethyl- and unsubstituted). Furthermore, the indole-N-methylated compound was generated and by using norephedrines and norpseudoephedrines as a chiral pool, 4-methyl-5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles were prepared which contained racemisation at the reacting C-atom. These compounds, as well as the ring-open amino-alcohols, were screened for their affinity to the hD₁-, hD₅-, hD_2L-, and hD₄-receptors (ç please check sentence). They had micromolar affinities for the receptors and showed the highest affinity to the D₁-subtype family. The cyclic compounds possessed the highest affinity, with the cyclopropylmethyl-(3c) and methyl-substituents (3e) being the most active of the tested compounds. Based on an intracellular cAMP-assay, the unsubstituted compound (at the azepine-N position) turned out to be an agonist for the D₁-and D₅-subtype family, whereas the substituted compounds showed (partial) agonistic, or even inverse agonistic activity.

A series of 7, 7′—alkylene-bridged dimers(7a—e) of the benz [d]indolo[3, 2-f]azecine derivative LE300 was synthesized. Affinity and functional activity at dopamine D₁ and D₂ receptors were estimated by radioligand binding and a functional Ca²⁺ assay. All the new bivalent ligands showed significant binding affinities to both D₁ and D₂ receptorswith an optimal distance between the two monomeric recognition unitsof 6 methylene moieties. The D₁/D₂-selectivity pattern was dependent on the spacer length. No (7a, b) or only moderate (7c—e) functional activity wasdetected for all bivalent compounds by measuring the inhibition of agonist-induced increase in intracellular Ca²⁺.

LE 300 represents a structurally novel type of antagonist acting preferentially at the dopamine D₁/D₅ receptors and the serotonin 5-HT_2A 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 β-phenylethylamines were treated with ethyl ω-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, andD₅ receptors and only moderate antagonistic activity at the 5-HT_2A 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.