Interactions of salsolinol and its mono-O-methylated analogs with adrenergic and dopaminergic receptors in the rabbit ear artery.

We have examined the action of the tetrahydroisoquinoline derivatives salsolinol, 6-O-methyl salsolinol (6-O-Me-Sal) and 7-O-methyl salsolinol (7-O-Me-Sal) on adrenergic and dopaminergic receptors in the isolated and perfused rabbit ear artery. The racemic form of the three compounds and the S-(--)-isomer of 6-O-Me-Sal were used. Salsolinol (0.3-10 micrometers) produced concentration-dependent inhibition of the vasoconstrictor response to electrical stimulation of the periarterial sympathetic nerves but did not inhibit the vasoconstrictor response to exogenous norepinephrine. The inhibitory effect of salsolinol on neurotransmission was antagonized by yohimbine, but not by sulpiride or propranolol. The dissociation constant (KB) for yohimbine acting as an antagonist of salsolinol was 98 +/- 8 nM. 6-O-Me-Sal and 7-O-Me-Sal did not affect the response to nerve stimulation or norepinephrine administration; however, these mono-O-methylated analogs of salsolinol antagonized the inhibition of neurotransmission produced by dopamine. The KB values for 6-O-Me-Sal and 7-O-Me-Sal acting as antagonists of dopamine were 1.3 +/- 0.2 and 6.4 +/- 0.31 microM, respectively. S-(--)-6-O-Me-Sal, with a KB value of 0.64 +/- 0.06 microM, was about twice as potent as racemic 6-O-Me-Sal. We conclude that salsolinol acts as an agonist on prejunctional alpha adrenergic receptors and that 6-O-Me-Sal and 7-O-Me-Sal act as antagonists on dopaminergic receptors.