Oleic Derivatives of Dopamine and Respiration

Abstract

Ventilatory inhibition is considered an undesirable pharmacological side effect of pharmacotherapy in neurodegenerative conditions underlain by brain dopamine deficiency. In this context, oleic derivatives of dopamine or N-acyl-dopamines are novel substances that may be of high therapeutic interest as having the ability to cross the blood-brain barrier and acting in dopamine-like manner. In the present study we seek to define the influence of N-acyl-dopamines on lung ventilation and its hypoxic responses in the rat. We found that N-oleoyl-dopamine decreased both normoxic and peak hypoxic ventilation in response to 8% acute hypoxia, on average, by 31% and 41%, respectively. Its metabolite, 3′-O-methyl-N-oleoyl-dopamine, caused a 15% ventilatory decrease each, whereas an oleic ester derivative, 3′-O-oleoyl-N-oleoyl-dopamine, caused 11% and 19% ventilatory decreases, respectively. All three N-acyl-dopamines investigated displayed an inhibitory effect on ventilation. The findings indicate that 3′-O-methyl-N-oleoyl-dopamine and 3′-O-oleoyl-N-oleoyl-dopamine performed better than N-oleoyl-dopamine in term of less ventilatory suppression, albeit the differences among the three compounds were modest. We conclude that N-acyl-dopamines are worthy of intensified explorations as potential carriers of dopamine molecule in view of the lack of clinically effective methods of dopamine delivery into the brain in neurodegenerative conditions.