Antidepressants phosphodiesterase inhibition

The stimulation of the octopaminergic nervous system of invertebrates is a proven strategy for the control of important pest species. This has been achieved in the past by the use of octopamine receptor agonists such as formamidine and imidazoline derivatives. However, other potential strategies to achieve this end include the inhibition of cyclic nucleotide phosphodiesterase, inhibition of the neural reuptake of octopamine, and inhibition of octopamine N-acetyltransferase. Using the American cockroach nervous system, formamidines were found to inhibit both the uptake and acetylation of octopamine, but not with a potency comparable to their effect on octopamine receptors. The tricyclic antidepressant, desipramine, and the benzylamine, xylamine, were the most active inhibitors of these octopamine removal systems. The pharmacological profiles for uptake and N-acetylation appear to be quite similar, but differ from that of the adenylate cyclase-linked octopamine receptor. 

Bobon D, Breulet M, Gerard-Vandenhove MA, Guiot-Goffioul F, Plomteux G, Sastre-y-Hernandez M, Schratzer M, Troisfontaines B, von Frenckell R, Wachtel H. Is phosphodiesterase inhibition a new mechanism of antidepressant action A double blind double-dummy study between rolipram and desiptamine in hospitalized major and/or endogenous depressives. Eur. Arch. Psychiatr. Neurol. Sci. 1988 238(l) 2-6. 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

But now, a strategy, used for the synthesis of derivative (622) (lit. synthesis (622) see in Ref. 555), which is the most efficient analog of the commercial drug rolipram with a broad spectrum of action (in particular, anti-inflammatory, antidepressant, neuroprotective, and immunodepressing effects), is presented in Scheme 3.286. (The principle action of rolipram is based on selective inhibition of adenosine monophosphate (AMP)-specific phosphodiesterase.) Derivative (622) is almost 10 times more efficient than rolipram, but the biological activity of (622) was determined only for the racemate (555). 

Houslay MD, Sullivan M, Bolger GB. The multlenzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family intracellular targeting, regulation, and selective Inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 1998 44 225-342. 

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