HP505

The effects of established and several novel antidepressant agents on brain monoamine oxidase [9001-66-5] A and B; high affinity synaptosomal uptake of norepinephrine [51-41-2], dopamine [51-61-6], and serotonin creatinine sulfate [971-74-4], and β-adrenergic receptor kinetics evaluated by (³H)-dihydroalprenolol binding to cortical membranes are described.Extremely weak in vitro inhibitory effects on rat brain mitochondrial MAO-type A or B were observed with (+) P74-1197 [59143-05-4] or (-) [75240-31-2] and HP-505 [59142-94-8], P77-2984 [72364-38-6], a 3-aryl-spirobenzothiophenepiperidine derivative, LM-5008 [63758-79-2], an indolylethylpiperidine, desipramine [50-47-5], nisoxetine [53179-07-0] and P76-2543 [75241-19-9], a 4-aryl-1,3 benzodiazapine.As anticipated, deprenyl [2323-36-6] showed potent substrate selective inhibition of MAO type B.LM-5008, P74-1197(+) and P77-2984 were potent selective inhibitors of serotonin synaptosomal uptake while nisoxetine, P76-2543 and (-)P74-1197 appeared to preferentially inhibit reuptake of norepinephrine.The kinetics (B_max and K_D) of (³H)-dihydroalprenolol binding were also studied following chronic administration of these same drugs (10 mg/kg, b.i.d.).After 10 days of treatment, heterogeneous results were obtained in that some compounds elicited changes in receptor d. and dissociation constant while others, such as nisoxetine, produced no kinetic alterations.While present biochem. antidepressant tests utilized in this study are designed to evaluate modulations of aminergic systems in terms of neurotransmitter availability, fluxes in concentration and attendant receptor recognition site sensitivities, the underlying mode(s) of action at the cellular level still require further clarification.

The synthesis and antihypertensive and diuretic activity of several N-sulfur derivatives of 3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] are reported. Benzenesulfenamide 3 possessed marked, species-specific diuretic and antihypertensive activity in rats.