Serotonin autoreceptors on dorsal raphe neurons: structure-activity relationships of tryptamine analogs

A series of indole-ethylamines were tested for their ability to suppress the spontaneous firing of single dorsal raphe serotonergic neurons in the rat. The compounds were all derivatives of either tryptamine or N,N-dimethyltryptamine possessing hydroxy or methoxy substituents on the benzene ring portion of the indole nucleus. Their activity was assessed using quantitative microiontophoresis or following systemic (intravenous) administration. The serotonin autoreceptor or so-called "S2 receptor" mediating the inhibition of raphe serotonergic neurons was found to exhibit a high degree of structural specificity among the closely related tryptamine analogs. The following structure-activity rules were demonstrated: (1) for either hydroxy or methoxy derivatives, the relative favorability of the ring positions conforms to the series 5 much greater than 4 greater than 6; (2) methoxy derivatives are more sensitive to a shift of the ring substituent from the 5- to the 4- or 6-positions than are hydroxy compounds; and (3) activity is enhanced by N,N-dimethylation. Furthermore, addition of a methyl group at the 7-position of 5-methoxy-N,N-dimethyltryptamine markedly reduces the activity of this potent agonist. Of the radioligands which label brain serotonin receptors, the pharmacological characteristics of D-[3H]lysergic acid diethylamide binding best correspond to those displayed by the S2 receptor as determined in the present physiological analysis, although sufficient data are not yet available to make a complete comparison.