Background: Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of CNS diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101.

Objective: We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders.

Results: AVN-101 is a very potent 5-HT7 receptor antagonist (Ki=153 pM), with slightly lesser potency towards 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2 — 2.0 nM). AVN-101 also exhibits a rather high affinity towards histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41 – 3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier (BBB) permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases.

Conclusion: The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer’s disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia and multiple sclerosis.