Chemical design of peripherally acting compounds.

1. Some guanidines, related in structure to mianserin and to 2-methyl-1,2,9,13b-tetrahydro-3H-dibenz[c,f]imadazo[1,5a] azepin-3-imine hydrobromide (WAL 801), have been synthesized and shown to be peripherally acting 5-HT2 antagonists. Structurally related compounds but not bearing a charged ionic group have been shown to have central activity. 2. Computer-aided molecular modelling has been used to establish a 5-HT2 pharmacophore. 3. The principle of exclusion from the CNS by incorporating a highly polar group to a biologically active molecule has been extended to the design and synthesis of a peripherally acting analgesic.

Influence of desipramine on the uptake and efflux of radiolabelled bretylium and bethanidine in the adventitial and media-intimal layers of rabbit aortic strips.

The desipramine-sensitive uptake (neuronal uptake) of 14C-bretylium and 14C-bethanidine into the rabbit aortic adventitial layer from 3 X 10(-6) M solutions increased with time during a 20 min incubation. For both compounds a neuronal uptake of 50 pmol/50 mg wet weight adventitia was associated with 10% block of the contractile response to field stimulation at 16 Hz and 150 pmol/50 mg with 60% block. The concentration of blocking agents inside the neuron at 50% blockade was calculated to be 260 X 10(-6) M, an 87-fold increase over the medium. The bretylium in the neuron decreased by 50% during 20 min washout, and bethanidine by 29%. Desipramine when added to the bath 20 min following the addition of the blocking agents led to a loss of bretylium but not of bethanidine from the adventitia. Desipramine had little or no effect on the uptake, washout or disposition of either blocking agent in the media-intimal layers. The data indicate that bretylium has a greater propensity than bethanidine to be lost from the neurons; however, it appears to be recycled back through the membrane via the amine pump more readily than bethanidine. The fact that conservative calculations indicate that the neuronal membrane slowly established a concentration of the blocking agents within the neuron that is known to produce rapid local anesthesia when topically applied to adrenergic nerve trunks and which approaches a concentration needed to inhibit sensory endings suggests that local anesthesia may play a role in the mechanism of neuron blockade.

Effects of bretylium on rat cardiac muscle: the electrophysiological effects and its uptake and binding in normal and immunosympathectomized rat hearts.

Bretylium produced electrophysiological effects on both rat atrium and ventricle in vitro at concentrations ranging from 2 times 10- minus 5 to 10- minus three M. Those effects included lengthening of action potential duration and effective refractory period; increasing effective refractory period/action potential duration; decreasing dv/dt of phase zero of the action potential and suppressing the action potential amplitude and overshoot. These effects, which could serve as a basis for the antiarrhythmic action of bretylium, were observed also in hearts from immunosympathectomized rats confirming a direct effect of this drug on the electrical properties of the cardiac muscle cells. In vivo and in vitro exposure of the myocardium to 14-C-bretylium showed that this drug is concentrated in cardiac ventricle and that this concentrating ability of the heart may be responsible for attaining effective antiarrhythmic concentrations in the myocardium at low plasma concentrations of the drug. Uptake of bretylium by the sympathetic nerves never amounted to more than 15% of the total bretylium binding by the cardiac ventricle and this neuronal uptake became insignificant compared to total bretylium uptake at concentrations greater than 10- minus 6 M. Subcellular distribution of the bretylium bound to the cardiac ventricle from immunosympathectomized rats suggested a binding to plasma membranes. Efflux studies indicate that this binding was tight, although reversible. These results indicate that underlying the antiarrhythmic effects of bretylium is an accumulation of the drug by cardiac muscle cells and a direct effect of the drug on the electrical properties of the cardiac muscle membrane independent of any action on the adrenergic neuron.