Gepirone (brand name Travivo) is an investigational azapirone antidepressant and anxiolytic drug in development for the treatment of major depressive disorder but has yet to be marketed. Like other azapirones, it acts as a selective partial agonist of the 5-HT1A receptor. Gepirone has been under development in the U.S. in an extended release form (referred to as Gepirone ER). It has been rejected multiple times by the FDA during the drug approval process and Phase III studies evaluating its use in the treatment of MDD were prematurely terminated. These were the initial Phase III studies of gepirone ER in MDD, and the effective dose range had not been determined. In March 2016, the FDA reversed its decision and gave gepirone ER a positive review, clearing the way for the drug to finally gain market approval in the U.S. In addition to its antidepressant and anxiolytic properties, gepirone has been found to improve symptoms of sexual dysfunction in men and women, similarly to the marketed 5-HT1A receptor agonist flibanserin. The pro-sexual effects appear to be independent of its antidepressant and anxiolytic effects. Mechanism of action studies have demonstrated that gepirone possesses a much greater selectivity for 5-HT1A receptors over dopamine D2 receptors. Long-term studies have shown that gepirone has a differential action at presynaptic (agonist) and post-synaptic (partial agonist) 5-HT1A receptors. Treatment with gepirone ER desensitizes presynaptic 5-HT1A receptors, which decreases serotonin autoregulatory inhibition and enhances activation of postsynaptic 5-HT1A receptors. As a partial agonist gepirone ER acts as an agonist when endogenous serotonin is not present and as an antagonist when endogenous serotonin is present. Overall, gepirone ER increases serotonin production when insufficient amounts are present, and decreases serotonin production when excess amounts are present. Gepirone has been tested in Phase II clinical trial as antidepressant medication for pharmacotherapy for cocaine dependent subjects.

Tapinarof (also known as benvitimod, WB-1001; GSK-2894512), an investigational therapeutic aryl hydrocarbon receptor modulating agent that selectively modulates the cytokine cascade deep under the skin, a process that rapidly decreases inflammations and skin plague. Tapinarof participated in clinical trials for the treatment of psoriasis and atopic dermatitis. Phase III clinical trials to evaluate the efficacy and safety of the cream for the topical treatment of plaque psoriasis (psoriasis) was terminated because of the business decision based on the need to prioritize and focus resources within GSK. In July 2018, Roivant subsidiary Dermavant Sciences purchased the rights for tapinarof. Besides, tapinarof participated in phase II clinical trials for patients with atopic dermatitis.

Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) (GNX) is the 3beta-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. GNX is an allosteric modulator of GABA(A) receptors acting through binding sites which are distinct from the benzodiazepine binding site. It has activity in a broad range of animal models of epilepsy. GNX has been shown to be well tolerated in adults and children. In early phase II studies, GNX has been shown to have activity in adult patients with partial-onset seizures and epileptic children with history of infantile spasms. It is currently undergoing further development in infants with newly diagnosed infantile spasms, in women with catamenial epilepsy, and in adults with refractory partial-onset seizures. Ganaxolone is a CNS-selective GABAA modulator being developed in three different dose forms (IV, capsule, and liquid) intended to maximize therapeutic reach to adult and pediatric patients in both acute and chronic care settings.Ganaxolone is a synthetic analog of endogenous allopregnanolone, which has been shown to be an effective anticonvulsant by restoring electrical balance to the seizing brain. While allopregnanolone’s anticonvulsant and anti-anxiety activities are well documented, allopregnanolone has the potential to convert back to its metabolic precursor progesterone, which could lead to hormonal side effects. Ganaxolone has been designed with an added methyl group that prevents back conversion to an active steroid which unlocks ganaxolone’s potential for chronic use. In preclinical studies, ganaxolone exhibited potency and efficacy comparable to allopregnanolone. Both ganaxolone and allopregnanolone bind to GABAA at the synaptic and extrasynaptic binding sites. Activity with extrasynaptic GABAA receptors are of particular importance for treating patients who developed tolerance to benzodiazepines and barbiturates. Ganaxolone binds to the GABAA receptors, which opens the pore to allow chloride ions to move into the postsynaptic neuron, leading to the inhibition of neurotransmission.

Samidorphan was developed as a sublingually bioavailable µ-opioid receptor antagonist. This drug participated in clinical trials for the treatment of Schizophrenia, Alcohol Dependence, and Binge Eating Disorder. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in phase II double blind, placebo-controlled, randomized studies in healthy adults. In addition, the combination of samidorphan (SAM) with buprenorphine (BUP) was studied in phase III clinical trial in patients with major depressive disorder (MDM). It was shown that the long-term treatment did not reveal any new safety findings and confirmed that the risk of abuse and dependence with BUP/SAM was low.

Viloxazine is an antidepressant drug was used to treat patients with depression. Viloxazine inhibits noradrenaline uptake. This drug was approved in some Europe countries, but not in the USA, but then it was discontinued because of competition from other drugs. In the frame of drug repositioning, Viloxazine participated in clinical trials for the treatment of attention deficit hyperactivity disorder. Phase II of trials was successfully passed.

Remimazolam is an intravenous benzodiazepine sedative-hypnotic with rapid onset and offset of action. This compound undergoes organ-independent metabolism to an inactive metabolite. Like other benzodiazepines, remimazolam can be reversed with flumazenil to rapidly terminate sedation and anesthesia. Phase I and II clinical trials have shown that remimazolam is safe and effective when used for procedural sedation. Phase III clinical trials have been completed investigating efficacy and safety in patients undergoing bronchoscopy and colonoscopy. The developer of this drug has suggested that intensive care unit sedation (beyond 24 hours) could be another possible indication for further development, since it is unlikely that prolonged infusions or higher doses of remimazolam would result in accumulation and extended effect.

Bristol-Myers Squibb developed Rimegepant, also known as BMS-927711. Rimegepant is a potent, selective, competitive and orally active calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine. Rimegepant has shown in vivo efficacy without vasoconstrictor effect; it is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Amisulpride, a benzamide derivative, shows a unique therapeutic profile being atypical antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisupride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In addition its antagonism at serotonin 5-HT7 receptors likely underlies the antidepressant actions. Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy.

Vibegron is a selective beta 3 adrenergic receptor (β3AR) agonist that is being developed in Japan jointly by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co., Ltd and in other regions worldwide (except in several other Asian countries) by Urovant Sciences for the treatment of overactive bladder (OAB). Vibegron potently activates human b3AR and increases cAMP levels, with an EC50 of 1.1 nM. Based on results from Japanese phase III trials, vibegron received approval in Japan in September 2018 for this indication. Vibegron, an active ingredient of Beova® Tablets, is a novel once-daily oral treatment for overactive bladder (OAB), acts selectively on the bladder's β3-adrenergic receptor, relaxes the bladder and enhances the urine collection, and consequently improves the symptoms of urgency, urinary frequency and urge urinary incontinence associated with OAB.

Istradefylline is a first-in-class adenosine A2A receptor antagonist antiparkinsonian agent and has been marketed as the brand name NOURIAST® in Japan since May 30, 2013. NOURIAST is indicated for the improvement of wearing-off phenomena in patients with Parkinson’s disease on concomitant treatment with levodopa-containing products.