Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of Monopropyl Analogs of 5-, 7-, and 8-[[(Trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: Central Dopamine and Serotonin Receptor Activity

Abstract

In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8-triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R-(+)-6 was found to be a potent and selective 5-HT1A (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 +/- 1.1%) appeared to be slightly lower than that of 2 (11.2 +/- 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.

Benzylimidazolines as h5-HT1B/1D Serotonin Receptor Ligands: A Structure−Affinity Investigation

“…16 With the exception of 4 and 5, there are relatively few new structural leads that might serve as templates for the development of novel 5-HT 1D agonists. Even the partial ergoline 5 bears some resemblance to sumatriptan; furthermore, 5-related aminotetralins with affinity for 5-HT 1D receptors typically bind with yet higher affinity at 5-HT 1A receptors 17 due to their close structural analogy to the prototypical 5-HT 1A agonist 2-(N,Ndi-n-propylamino)tetralin (7). Clearly, new lead structures would be useful for the continued development of novel 5-HT 1D ligands.…”

Physiologically active compounds interacting with serotonin (5-hydroxytryptamine) receptors

“…According to some data, it is in the size of this domain that 5-HT 1D/1B receptors differ from the 5-HT 1A receptor, 113 although some of compounds mentioned, as expected, manifest low affinities for the latter. It is noteworthy that the introduction of a triflate group (compounds 50), which is bioisosteric to the carboxy or the methoxy group, 114 increases the selectivity towards 5-HT 1D receptors 10 ± 15-fold in comparison with 5-HT 1B receptors. 115 It is of note that until recently the ability of the substituent in position 5 to be involved in the formation of a hydrogen bond was thought to be a necessary prerequisite for high affinity, since virtually all presently known 5-HT 1D receptor agonists have at least one heteroatom (N, O or S) in this position.…”

ω-Transaminases for the amination of functionalised cyclic ketones

“…The frequent occurrence of such chiral amines has also highlighted interest in their preparation as synthons for use in the pharmaceutical sector. 7,[10][11][12] In addition more recently a variety of organocatalytic, metal-dependent as well as chemo-enzymatic dynamic kinetic resolution methods have been developed to produce enantiopure amines. 8,9 Traditionally single isomer chiral amines are generated from racemic mixtures using crystallisation methods, or they can be synthesised using chiral auxiliaries.…”

“…8,9 Traditionally single isomer chiral amines are generated from racemic mixtures using crystallisation methods, or they can be synthesised using chiral auxiliaries. 7,[10][11][12] In addition more recently a variety of organocatalytic, metal-dependent as well as chemo-enzymatic dynamic kinetic resolution methods have been developed to produce enantiopure amines. [13][14][15] The requirement for metals in some of these systems such as lipase-catalysed dynamic kinetic resolutions is however a major backdraw when considering the sustainability of the process.…”