Development of the First Ultra-Potent "Capsaicinoid" Agonist at Transient Receptor Potential Vanilloid Type 1 (TRPV1) Channels and Its Therapeutic Potential

University of Florence, Florens, Tuscany, Italy
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 03/2005; 312(2):561-70. DOI: 10.1124/jpet.104.074864
Source: PubMed


Olvanil (N-9-Z-octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lack the pungency of capsaicin and was developed as an oral analgesic. Vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety compared with the more powerful TRPV1 agonists, like the structurally complex phorboid compound resiniferatoxin. We have modified the fatty acyl chain of olvanil to obtain ultra-potent analogs. The insertion of a hydroxyl group at C-12 yielded a compound named rinvanil, after ricinoleic acid, significantly less potent than olvanil (EC(50) = 6 versus 0.7 nM), but more versatile in terms of structural modifications because of the presence of an additional functional group. Acetylation and phenylacetylation of rinvanil re-established and dramatically enhanced, respectively, its potency at hTRPV1. With a two-digit picomolar EC(50) (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described with potency comparable with that of resiniferatoxin (EC(50), 11 pM). Benzoyl- and phenylpropionylrinvanil were as potent and less potent than PhAR, respectively, whereas configurational inversion to ent-PhAR and cyclopropanation (but not hydrogenation or epoxidation) of the double bond were tolerated. Finally, iodination of the aromatic hydroxyl caused a dramatic switch in functional activity, generating compounds that behaved as TRPV1 antagonists rather than agonists. Since the potency of PhAR was maintained in rat dorsal root ganglion neurons and, particularly, in the rat urinary bladder, this compound was investigated in an in vivo rat model of urinary incontinence and proved as effective as resiniferatoxin at reducing bladder detrusor overactivity.

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Available from: Marcello Trevisani
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    • "C57Bl/6 male mice (Harlan, Udine, Italy) were used. Rinvanil (synthesized as reported; Appendino et al, 2005) or capsazepine (Tocris, Minneapolis, MN, USA) was dissolved in dimethyl sulfoxide (DMSO) and injected intraperitoneally at the indicated doses. Tb and skin temperature was measured by means of a rectal or skin probe (Harvard Apparatus, Holliston, MA, USA). "
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    ABSTRACT: Although treatment of stroke patients with mild hypothermia is a promising therapeutic approach, chemicals inducing prompt and safe reduction of body temperature are an unmet need. We measured the effects of the transient receptor potential vanilloid-1 (TRPV1) agonist rinvanil on thermoregulation and ischemic brain injury in mice. Intraperitoneal or intracerebroventricular injection of rinvanil induces mild hypothermia that is prevented by the receptor antagonist capsazepine. Both intraischemic and postischemic treatments provide permanent neuroprotection in animals subjected to transient middle cerebral artery occlusion (MCAo), an effect lost in mice artificially kept normothermic. Data indicate that TRPV1 receptor agonists are promising candidates for hypothermic treatment of stroke.
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    • "The TRPV1 receptor is a target for a large heterogeneous group of natural compounds including capsaicinoids such as capsaicin and dihydrocapsaicin (DHC) from chili pepper, piperine from black pepper, resiniferatoxin (RTX), ginsenosides, evodiamine and others that acts as agonists [20]. In addition potent synthetic agonists have been developed including rinvanil [21], MSK-195 [22], arvanil [23], and olvanil [24]. Interestingly, administration of TRPV1 agonists has been demonstrated to induce hypothermia in rats [25,26]. "
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    ABSTRACT: The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion. Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours. Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.
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    • "On the other hand, compounds that at the same time behave as inverse agonists at CB 2 receptors and agonists at TRPV1 receptors, particularly when not too potent as vanilloid agonists, are expected to be devoid of most of the undesired effects exhibited by arvanil and O-1816, and to maintain efficacy as anti-inflammatory agents. We have now identified two compounds endowed with these pharmacological properties, both obtained by chemical modification of PhAR [28], a compound showing ultra-potent activity at TRPV1 channels but weak affinity at CB 2 receptors. "
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