Abstract
Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements – SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition. However, selectivity over non-pathogenic enzyme family members, TPH2, phenylalanine hydroxylase, and tyrosine hydroxylase has hampered therapeutic development. Here we describe the site/sequence, biochemical, and biophysical characterization of a novel allosteric site on TPH1 through which selectivity over TPH2 and related aromatic amino acid hydroxylases is achieved. We demonstrate the mechanism of action by which novel compounds selectively inhibit TPH1 using surface plasma resonance and enzyme competition assays with both tryptophan ligand and BH4 co-factor. We demonstrate 15-fold greater potency within a human carcinoid cell line versus the most potent known TPH1/2 non-specific inhibitor. Lastly, we detail a novel canine in vivo system utilized to determine effective biologic inhibition of newly synthesized 5-HT. These findings are the first to demonstrate TPH1-selective inhibition and may pave the way to a truly effective means to reduce pathologic 5-HT and thereby treat complex remodeling diseases such as PAH.
Highlights
Serotonin (5-HT) has 15 receptors (5-HTR) divided into seven families, whose wide distribution and function both peripherally and within the central nervous system indicate the complexity of this signaling system (Berger et al, 2009)
Knockout studies have demonstrated the distribution of tryptophan hydroxylase (TPH) isoforms in the body – tryptophan hydroxylase 1 (TPH1) primarily expressed in the pineal gland and enterochromaffin cells of the gut, whereas TPH2 is restricted to neuronal cells (Cote et al, 2003; Walther et al, 2003; Patel et al, 2004)
A breakthrough in pharmacologic inhibition of TPH was achieved with the discovery of molecules whose expanded pCPA core gained selectivity over related amino acid hydroxylases
Summary
Serotonin (5-HT) has 15 receptors (5-HTR) divided into seven families, whose wide distribution and function both peripherally and within the central nervous system indicate the complexity of this signaling system (Berger et al, 2009). Clinical data in carcinoid syndrome using pCPA revealed the liabilities of non-selective TPH inhibition, where TPH2 inhibition has been retrospectively attributed to psychosis observed in some patients (Engelman et al, 1967) More recent molecules such as Telotristat etiprate, which more potently inhibits TPH1/2 than pCPA, with better selectivity over related aromatic amino acid hydroxylases, have demonstrated efficacy in carcinoid syndrome trials showing some symptomatic improvements and good tolerability (Kulke et al, 2014). The efficacy of such a therapeutic strategy is limited in diseases where the principal site of pathologic 5-HT production is distal to the gut, such as pulmonary endothelium in PAH or lung metastases in carcinoid syndrome
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