This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
Chronic pain is a major health concern that costs the US more than $635 billion per year (Gaskin and Richard, (2012) J. Pain 13:715-724). In addition to the financial impact, patients with chronic pain suffer extreme physical, emotional, and social burdens. For example, individuals often become socially isolated and confined to home as a result of their chronic pain that is not well-controlled by today's available treatments. The drugs used for the management of chronic pain include opioid analgesics, neuronal stabilizers such as anticonvulsants, and antidepressants. Opioids are the most widely used, and a recent NIH report indicates that there are significant problems associated with long-term opioid therapy for chronic pain (Volkow and McLellan (2016) N Engl J Med 374:1253-1263.). None of the agents provide sufficient relief to allow patients to return to their normal activity level. Moreover, current pharmaceutical industry has retreated from studying novel pain therapeutics due to the enormous risk (Skolnick and Volkow (2016) Neuron 92:294-297.). These observations indicate an essential need to identify new agents acting on unique targets in the war on chronic pain.
Adenylyl cyclases are enzymes that catalyze the production of cyclic adenosine monophosphate, an important biological messenger. There are nine different membrane-bound human adenylyl cyclase isoforms, each with slightly different attributes. In particular, adenylyl cyclase 1 (AC1) is highly expressed in the hippocampus as well as in regions of the brain associated with pain. AC1 knock out animals show reduced neuropathic and inflammatory pain. Additionally, AC1 knock out mice show less reward when given opioids and show reduced symptoms of opioid dependence during withdrawal. Additional reports suggest that AC1 inhibition may also provide a useful therapeutic intervention for alcohol use disorder and autism (Bosse K E et al., J. Pharmacol. Exp. Ther. 2017, 363 (2) 148-155; Sethna F., et al. Nat. Commun. 2017, 8, 14359).
Unfortunately, until now, the selective inhibition of ACs has not been achieved, and simultaneous inhibition of multiple adenylyl cyclase isoforms would likely result in significant adverse effects. There are unmet needs for better and safer medications targeting adenylyl cyclases for various therapeutic uses.