5-Nonyloxytryptamine oxalate

Nonyloxytryptamine mimics polysialic acid and modulates neuronal and glial functions in cell culture.[Pubmed:23957498]

J Neurochem. 2014 Jan;128(1):88-100.

Polysialic acid (PSA) is a major regulator of cell-cell interactions in the developing nervous system and in neural plasticity in the adult. As a polyanionic molecule with high water-binding capacity, PSA increases the intercellular space generating permissive conditions for cell motility. PSA enhances stem cell migration and axon path finding and promotes repair in the lesioned peripheral and central nervous systems, thus contributing to regeneration. As a next step in developing an improved PSA-based approach to treat nervous system injuries, we searched for small organic compounds that mimic PSA and identified as a PSA mimetic 5-Nonyloxytryptamine oxalate, described as a selective 5-hydroxytryptamine receptor 1B (5-HT1B ) agonist. Similar to PSA, 5-nonyloxytryptamine binds to the PSA-specific monoclonal antibody 735, enhances neurite outgrowth of cultured primary neurons and process formation of Schwann cells, protects neurons from oxidative stress, reduces migration of astrocytes and enhances myelination in vitro. Furthermore, nonyloxytryptamine treatment enhances expression of the neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM and reduces expression of the microtubule-associated protein MAP2 in cultured neuroblastoma cells. These results demonstrate that 5-nonyloxytryptamine mimics PSA and triggers PSA-mediated functions, thus contributing to the repertoire of molecules with the potential to improve recovery in acute and chronic injuries of the mammalian peripheral and central nervous systems. Polysialic acid (PSA) plays important roles in nervous system development, as well as synaptic plasticity and regeneration in the adult. 5-Nonyloxytryptamine oxalate (5-NOT) mimics PSA and triggers PSA-mediated functions in neurons and glial cells. 5-NOT stimulates neuritogenesis, myelination and Schwann cell migration. This study sets the basis to develop a PSA-mediated therapy of acute and chronic nervous system diseases.

Binding of O-alkyl derivatives of serotonin at human 5-HT1D beta receptors.[Pubmed:8568822]

J Med Chem. 1996 Jan 5;39(1):314-22.

In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1D beta receptors (Ki < 5 nM) but demonstrate less than 50-fold selectivity relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT1A receptors whereas groups longer than nine carbon atoms lead to compounds with reduced affinity at 5-HT1D beta receptors. 5-(Nonyloxy)tryptamine (10) represents a compound with optimal 5-HT1D beta affinity (Ki = 1 nM) and selectivity (> 300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1D beta Ki = 2.3 nM) but with greater (i.e, 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or beta-carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1D beta versus 5-HT1D alpha sites; nevertheless, compounds 10 (recently shown to have as a 5-HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.