DDD-028: A potent, neuroprotective, non-opioid compound for the treatment of diabetic neuropathy.

Diabetic neuropathy (DN) is a painful, chronic ailment that affects a large segment of diabetic population worldwide. Current medications such as pregabalin or duloxetine treat only the pain symptom associated with DN, but not the underlying nerve damage. DDD-028 (1) is a small molecule that displays potent pain-relieving activity in streptozotocin (STZ)-induced rodent model of DN. Combined with other studies indicating that DDD-028 suppresses astrogliosis and nerve damage induced by the anti-cancer drug, paclitaxel, the present study suggests that DDD-028 would be useful as a disease modifying therapeutic in the treatment of DN. The 3-dimensional structure of DDD-028 was confirmed by single crystal X-ray crystallography.

The synthesis and comparative receptor binding affinities of novel, isomeric pyridoindolobenzazepine scaffolds.

Compounds 7, 8, and 9, derived from the novel scaffolds 3, 5, and 6, were synthesized and evaluated in vitro. The b,c→c,d shift of the E-phenyl ring resulted in a large decrease (ca. 20- to 1000-fold) in binding to the 5-HT2A, 5-HT2C and H2, receptors, and a modest decrease (ca. 10- to 20-fold) in binding to the 5-HT5A, D2, D5, and α1D, receptors. The b,c→d,e shift resulted in a large decrease in binding to the 5-HT1D, 5-HT2C, 5-HT6, and H1 receptors, a modest decrease in binding to 5-HT1A, 5-HT5A and D2, D5, α2B, and H2 receptors, and a large increase in affinity to the 5-HT3, 5-HT6, and σ1 receptors.

DDD-028: a potent potential non-opioid, non-cannabinoid analgesic for neuropathic and inflammatory pain.

DDD-028 (4), a novel pentacyclic pyridoindolobenzazepine derivative was evaluated in vitro for receptor binding affinity and in vivo for analgesic activity using rodent models of neuropathic and inflammatory pain. DDD-028 does not bind to opioid, cannabinoid, dopamine, or histamine receptors. DDD-028 is very active even at the low oral dose of 1-5 mg/kg in both neuropathic, (spinal nerve ligation and chronic constriction injury) and inflammatory (Complete Freund's Adjuvant Induced) models of pain. DDD-028 appears to be about 6-fold more potent than pregabalin and indomethacin. Visual observation of all the animals used in these studies indicated that DDD-028 is well tolerated without any sedation. Thus, DDD-028 seems to be a promising candidate for the treatment of neuropathic and inflammatory pain without the possible side effects or abuse potential associated with opioid or cannabinoid activities.

Broad-spectrum neuroprotection exerted by DDD-028 in a mouse model of chemotherapy-induced neuropathy.

ABSTRACT: Neurotoxicity of chemotherapeutics involves peculiar alterations in the structure and function, including abnormal nerve signal transmission, of both the peripheral and central nervous system. The lack of effective pharmacological approaches to prevent chemotherapy-induced neurotoxicity necessitates the identification of innovative therapies. Recent evidence suggests that repeated treatment with the pentacyclic pyridoindole derivative DDD-028 can exert both pain-relieving and glial modulatory effects in mice with paclitaxel-induced neuropathy. This work is aimed at assessing whether DDD-028 is a disease-modifying agent by protecting the peripheral nervous tissues from chemotherapy-induced damage. Neuropathy was induced in animals by paclitaxel injection (2.0 mg kg -1 i.p). DDD-028 (10 mg kg -1 ) and the reference drug, pregabalin (30 mg kg -1 ), were administered per os daily starting concomitantly with the first injection of paclitaxel and continuing 10 days after the end of paclitaxel treatment. The behavioural tests confirmed the antihyperalgesic efficacy of DDD-028 on paclitaxel-induced neuropathic pain. Furthermore, the electrophysiological analysis revealed the capacity of DDD-028 to restore near-normal sensory nerve conduction in paclitaxel-treated animals. Histopathology evidence indicated that DDD-028 was able to counteract effectively paclitaxel-induced peripheral neurotoxicity by protecting against the loss of intraepidermal nerve fibers, restoring physiological levels of neurofilament in nerve tissue and plasma, and preventing morphological alterations occurring in the sciatic nerves and dorsal root ganglia. Overall, DDD-028 is more effective than pregabalin in preventing chemotherapy-induced neurotoxicity. Thus, based on its potent antihyperalgesic and neuroprotective efficacy, DDD-028 seems to be a viable prophylactic medication to limit the development of neuropathies consequent to chemotherapy.

Pain Relieving and Neuroprotective Effects of Non-opioid Compound, DDD-028, in the Rat Model of Paclitaxel-Induced Neuropathy.

Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1-25 mg kg-1) or repeatedly (10 mg kg-1) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN.