It is conceptually attractive to target systems that drive negatively reinforced drug seeking and taking for clinical development of therapeutics, but there are numerous challenges to realizing that potential. Technical and practical issues differ markedly between the systems. At one end of the spectrum, NK1R antagonists with acceptable safety, tolerability, and ability to engage central targets are widely available and have enabled initial clinical trials. At the other, selective non-peptide CRF2R ligands are still lacking, posing challenges even for early preclinical target validation studies.
