Absence of bioactivity of lipid derivatives of serotonin.

BACKGROUND: Serotonin (5-HT) and its receptors are present in central, the brain stem, and peripheral, the carotid body, tissues controlling the ventilatory responses to hypoxia. The exact action of serotonin and its nature are, however, unsettled. We hypothesized that the discrepant results on the ventilatory action of serotonin could be caused by the inability of serotonin to penetrate into the brain or the plasma membrane lipid bilayers, the target site of signal transduction cascades, after its exogenous administration. OBJECTIVE: To study the penetrability of novel lipid derivatives of serotonin of varying fatty acid chain length and number of saturated/unsaturated bonds, the oleic, caprylic, and caprolic amides of 5-HT, into the brain, and their functional effects on the hypoxic ventilatory response in awake rats after systemic administration. MATERIAL AND METHODS: Adult Wistar rats were used for the experiments. In the biochemical part of the study, the presence and stability of the compounds tested, after i.p. injection, was assessed in brain extracts using spectrophotometry and thin-layered chromatography. In the functional part, the ventilatory responses to 8 and 12% hypoxia were compared before and 1 h after the compound administration using a whole body plethysmography. RESULTS: The "lipidized" serotonin compounds turned out to be stable in brain extracts in vitro for up to 3 h of the test. However, we could not substantiate the presence of any of the compounds in the brain, with either method used, after i.p. administration. Likewise, none of the compounds had any appreciable effect on the profile of the stimulatory hypoxic ventilatory response. CONCLUSIONS: Synthetically attaching lipophilic groups to the serotonin molecule does not make it penetrate into the brain. The lack of serotonin penetrability likely depends on the planarity of its molecule, as it does not seem to depend on the size, number of carbons or bond saturation of the "lipidized" molecules. Such molecules do not directly interfere with the carotid chemoreceptor-mediated hypoxic ventilatory response. The study failed to substantiate the bioactive potential of the lipid derivatives of serotonin.

Membrane association of N-oleoyl-dopamine in rat brain.

N-oleoyl-dopamine (OLDA) belongs to a novel class of bioactive amides of fatty acids. The compound, a lipid derivative of dopamine, holds promise as a potential prodrug or carrier of dopamine into the brain. In this context, a key issue concerning OLDA is the integrity of the compound once it enters the brain. We addressed this issue in the current study by assessing the propensity of OLDA for hydrolysis in rat brain tissue in vitro. The brains were dissected from surgically anesthetized rats after they had been sacrificed by perfusion with physiological saline through the heart. Membrane fractions of brain tissue were isolated and incubated with 1 mmol/l OLDA. Stability of the OLDA molecule was assessed from the spectrophotometric recordings of OLDA spectra in membrane fractions at hourly time points for up to 24 hours. The methodological assumption was that any major change in the shape of the OLDA spectrum would point to a structural, and thus also possibly functional, alteration of the molecule. We found that the OLDA spectrum remained unchanged in the assays for up to 17 h of incubation. We conclude that OLDA strongly resists hydrolysis in brain membrane fractions. The results suggest that dopamine-like biological effects of OLDA might have to do with the interaction of the integral OLDA compound, rather than a dissociated-off dopamine moiety, with the dopaminergic system.

Fatty acid acylation of dopamine in the carotid body.

In this article, we put forward a hypothesis concerning the assembling and storage of dopamine molecules in the dense-core vesicles of the carotid body chemoreceptor cell. We posit that dopamine molecules are packed and sustained in the vesicular form due to the formation of N-acyldopamine, a condensation product of fatty acid acyl chain and dopamine at the amino group of the latter. N-acyldopamine would then be stored in a micelle-like supramolecular structure formed due to self-association through the hydrophilic dopamine headgroups. This hypothesis may help explain the perennial problem of the role of dopamine in chemoception. It also draws attention to the possibility of the existence of neurotransmitters in the N-acylated form. This could lead to the design of acylated compounds that would play a role of prodrugs slow-releasing active substances by hydrolysis into the desired environment.