Discovery of Spiro[cyclohexane-dihydropyrano[3,4‑<i>b</i>]indole]-amines as Potent NOP and Opioid Receptor Agonists

Abstract

We report the discovery of spiro­[cyclohexane-pyrano­[3,4-<i>b</i>]­indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone <b>1</b> and tryptophol in an oxa-Pictet–Spengler reaction led to the formation of spiroether <b>2</b>, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of <b>1</b>, which resulted in alcohols <b>3</b>–<b>5</b>, ethers <b>6</b> and <b>7</b>, amines <b>8</b>–<b>10</b>, <b>22</b>–<b>24</b>, and <b>26</b>–<b>28</b>, amides <b>11</b> and <b>25</b>, and urea <b>12</b>, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors