Relative activities of substances related to 5-hydroxytryptamine as depolarizing agents of superior cervical ganglion cells.

Membrane potential changes evoked by 5-Ht and related substances were recorded by the sucrose-gap method from rabbit ganglia superfused with Krebs solution at 20 degrees C. A solution of the substance under test was injected into the superfusion stream. The activity of 23 substances was compared to that of 5-HT in respect of depolarizing capacity. 0.01 mumol 5-HT produced a near-threshold depolarization, while 0.6-0.8 mumol induced a maximal one. Some 5-HT analogues evoked prolonged responses distinctly different from the rapid depolarization and repolarization characteristic of 6-HT, while others were inactive. Compounds di- or trimethylated at the side-chain nitrogen atom were capable in addition of activating nicotinic receptors. The results suggest that: (1) the optimal requirements for activating ganglionic 5-HT receptors are a hydroxyl group at position 5 on the indole nucleus and a side-chain bearing an ethylamine amino group; (2) methyl substituents around the terminal nitrogen atom are well tolerated and a quaternary nitrogen may increase activity at the 5-HT receptor; and (3) substitution of a methyl group at carbon atom 2 of the indole nucleus reduces activity. A limitation of the technique is the difficulty of obtaining more than one dose-response curve from a particular preparation; a reduction in potency due to lower affinity cannot be readily distinguished from one due to lower intrinsic activity.