Monday, June 11, 2012

Pharmacology of N-Isopropyloctopamine

N-Isopropyloctopamine (Betaphrine, Isopropylnorsynephrine) is a chemically modified version of octopamine which possesses a more favorable pharmacodynamic profile. It was made famous in the 2011 study which examined the effects of Bitter Orange extracts on lipolysis. The authors noted:
...their common isopropyl derivative, isopropylnorsynephrine (also named isopropyloctopamine or betaphrine), was clearly lipolytic: active at 1 μg/ml and reproducing more than 60% of isoprenaline maximal effect in human adipocytes. This compound, not detected in C. aurantium, and which has few reported adverse effects to date, might be useful for in vivo triglyceride breakdown. [1]

Pharmacodynamics, Pharmacokinetics, & Structural Activity
Before we analyze N-isopropyloctopamine, we should review its chemical cousin: Octopamine.

Octopamine is a very specific, and weak, beta-3-receptor agonist in mammals [2, 3]. It has no physiologic ability to activate any other adrenergic receptor. Unfortunately, its ability to activate beta3 receptors in mammals does not translate to fat loss in humans. In the study Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells, the authors revealed:
Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists.

Another study by Visentin et al. noted:
Human subcutaneous adipocytes constituted another model in which octopamine hardly activated lipolysis and did not inhibit insulin action. However, octopamine was able to activate glucose uptake into these cells in an oxidation-dependent manner...[3]

What this means is that not only was octopamine not able to activate any lipolysis in human fat cells, but that it was distinctly lipogenic by enhancing insulins ability to drive glucose into adipose tissue.

N-isopropyloctopamine (NIPO), on the other hand, possesses a bulky N-alkyl group which alters its receptor dynamics completely. Instead of relying on beta-3-receptor agonism for its induction of lipolysis, N-isopropyloctopamine fully agonizes the beta-1 & beta-2 receptor.
This compound was a highly beta selective, direct-acting adrenergic agonist,...[and] without appreciable selectivity for either beta-1 or beta-2 receptors [4] 
In humans, the beta-3 receptor is a very poor target for fat loss, whereas beta-2 agonism is more than adequate. Unfortunately, although NIPO fully agonizes beta adrenergic receptors, it is very weak:  "approximately 200- and 440-fold less potent than isoproterenol. [4]" Kinetically, its bioavailability is likely extremely poor - as is the case most para-hydroxylated phenylethylamine derivatives. Similarly, the para-hydroxyl also precludes BBB penetration, and so central effects like euphoria, increased attention, or insomnia, will be absent. Lastly, although the addition of the isopropyl group extends its half-life relatively, it will still be quite low (30 min - 2 hours maximum).

Ultimately, N-isopropyloctopamine will not likely produce exceptional results - especially in the context of fat loss. Furthermore, although N-isopropyloctopamine is offered in various fat burning/energy suppplements, it is explicitly non-FDA and non-DSHEA approved. The good news is that it has no appreciable alpha adrenergic agonism, and so signs of symptoms of high blood pressure will likely be absent [4].