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Potential Compounds to treat PSSD

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1 Potential Compounds to treat PSSD on Sun Jan 04, 2015 11:56 pm

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A novel phenyl-piperazine drug that is a pre-synaptic 1A serotonin agonist (lowering serotonin and presumably, raising dopamine) and a 5-HT1A post-synaptic antagonist - thus allowing for further dopamine enhancement by simultaneously blocking the 1A-inhibition of dopamine.

Lemme explain how this works.

Pre-synaptic 5-HT1A receptors inhibit serotonin release by acting as autoreceptors; eliciting negative feedback on serotonergic neurons, literally telling the brain, when serotonin binds to this receptor, decrease itself and it's release.

POST-SYNAPTIC 5-HT1A receptors on the other hand - inhibit dopamine when serotonin binds to it, and have other totally separate endocrine effects - including increasing corticosterone;cortisol - and also raising prolactin and beta-endorphin.

Antagonizing the post-synaptic 1A's would then decrease cortisol and prolactin, reduce excessive endorphin activity , and boost dopamine levels and testosterone.

This would beneficial on the entire sexual circuitry in both men and women.

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An extremely potent, in fact, the most potent 5-HT1A antagonist that has been developed to date, and a dual dopamine D4 agonist....D4 agonists themselves have been shown to induce penile erection, and have pro-sexual effects in terms of behavior as well, so this coupled with 5-HT1A antagonism may remove the barrier requiring dopamine to be boosted by other means, seeing as it basically replaces the effects of dopamine at one of it's most pro-sexual receptors, and simultaneously stops the inhibition of dopamine by serotonin, at least partially.

Eur J Neurosci. 2006 Oct;24(7):2021-30.
PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain.
Melis MR1, Succu S, Sanna F, Melis T, Mascia MS, Enguehard-Gueiffier C, Hubner H, Gmeiner P, Gueiffier A, Argiolas A.
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Abstract
PIP3EA (2-[4-(2-methoxyphenyl)piperazin-1-yl-methyl]imidazo[1,2-a]pyridine) and PD-168077 (N-[4-2-cyanophenylpiperazin-1-ylmethyl]-3-methylbenzamide maleate), two selective dopamine D4 agonists, administered systemically, intracerebroventricularly or into the paraventricular nucleus of the hypothalamus induce penile erection in male Sprague-Dawley rats. A U-inverted dose-response curve was found with either compound when given subcutaneously (1-100 microg/kg) or intracerebroventricularly (0.1-20 microg/rat), but not into the paraventricular nucleus (10-200 ng/rat). The pro-erectile effect of PIP3EA and of PD-168077 occurs concomitantly with an increased nitric oxide (NO) production in the paraventricular nucleus, as measured by the increased concentration of nitrites and nitrates found in the dialysate obtained from the paraventricular nucleus by intracerebral microdialysis. These effects of PIP3EA and PD-168077 were reduced by L-745,870 (3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo[2,3-b]pyridine trihydrochloride), a selective dopamine D4 receptors antagonist, by omega-conotoxin, a blocker of voltage-dependent Ca2+ channels of the N-type, by S-methyl-thiocitrulline, a neuronal nitric oxide synthase inhibitor, and by d(CH2)5Tyr(Me)2-Orn8-vasotocin, an oxytocin receptor antagonist, given into the lateral ventricles, but not into the paraventricular nucleus. Comparison of the dose-response curves of PIP3EA and PD-168077 revealed that PIP3EA is as potent as PD-168077 when given into the paraventricular nucleus, but more potent when given systemically. However, both compounds are less efficacious (e.g. induce a lower number of penile erection episodes) than apomorphine, a classical mixed dopamine receptor agonist, irrespective of the route of administration. These results confirm previous findings showing that central D4 receptors mediate penile erection and show that dopamine D4 receptor agonists act in the paraventricular nucleus to facilitate penile erection by increasing central oxytocinergic neurotransmission.
PMID: 17067298 [PubMed - indexed for MEDLINE]

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