A structure-activity study of the transport sites for the hypothalamic and striatal catecholamine uptake systems. Similarities and differences.

A series of eight substrate molecules (substituted phenethylamines, guanethidine, and bretylium) had slightly less affinity for striatal than for hypothalamic synaptosomal uptake receptors as judged by ratios of striatal (s) to hypothalamic (h) IC50 values (s/h average = 3.9; range 2.0--6.0). Catecholamine uptake in striatum was very insensitive to tricyclic antidepressant inhibitors, whereas catecholamine uptake in hypothalamus was very sensitive to these agents (s/h average = 233; range 24--570). By way of contrast with both the substrates and the tricyclic inhibitors, the inhibitors with less rigidly fixed rings or analogous groups (deoxypipradrol, methylphenidate, cocaine) were potent in both brain preparations (s/h average = 1.2; range 0.6--2.3). It is concluded that the rings of nontricyclic inhibitors are able to bind to appropriate hydrophobic binding groups in both receptors, that these receptive groups have different topography in striatum and in hypothalamus, and that the topography in the striatum is incompatible with binding tricyclic systems. The data also indicate that there is great similarity, if not identity, in the receptive area for substrates in striatum and hypothalamus. Although the substrates and inhibitors bind to some groups in common in this substrate receptive area, it is the surrounding hydrophobic molecular environment that is clearly different and permits the phenomenon of selective blockade with drugs.

Concerning the role of the amine pump of the adrenergic innervation of rabbit aorta in sustaining the neuron blockade produced by bethanindine and bretylium.

Adrenergic neuron blockade produced in rabbit aortic strips by bretylium and bethanidine has been studied. Differences were noted in the characteristics of approximately equal, strong neuron blockade produced by bretylium was readily reversed by washout of the drug from the tissue bath whereas blockade produced by bethanidine was slowly reversed. Desmethylimipramine prevented the onset of blockade from bretylium whereas it only delayed the onset of blockade due to bretylium but only slightly antagonized an established blockade due to bethanidine. It is suggested that the differences observed between these two neuron blocking agents are the result of their differential retention inside the neuron: bretylium is not firmly bound, leaks out of the neuron and goes through a process of recycling across the cell membrane, while bethanidine is more firmly bound inside the neuron than bretylium, only slowly leaks out of the neuron and is not recycled back across the cell membranes.