Synthesis and Evaluation of Aryl-Naloxamide Opiate Analgesics Targeting Truncated Exon 11-Associated μ Opioid Receptor (MOR-1) Splice Variants

Abstract

3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3′or 4′ position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower δ opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity.

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

“…The importance of 6TM variants in IBNtxA analgesia has been established (9)(10)(11)(12). We now have extended our studies of these truncated forms of the mu opioid receptor to explore other classes of analgesics.…”

Mu Opioids and Their Receptors: Evolution of a Concept

“…In addition to several full-length variants with predicted protein sequences identical to MOR-1 itself (i.e., mMOR-1H, mMOR-1i, mMOR-1J), these exon 11-associated variants include a number of truncated proteins predicting only six transmembrane domains. Initially considered of questionable relevance, recent work using an exon 11 knockout mouse now reveals that they are important in the actions of many established opioid analgesics (section VIII.C.3.b) Majumdar et al, 2011Majumdar et al, , 2012.…”

“…The functional significance of these splice variants has been further strengthened by the actions of a series of unique analgesics based upon 39-iodobenzoyl-6b-naltrexamide (IBNtxA) (Fig. 22) (Majumdar et al, 2011(Majumdar et al, , 2012. Despite being a naltrexone derivative, this ligand is 10-fold more potent an analgesic than morphine.…”

Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

“…In contrast, morphine and methadone retain full analgesic activity in the exon 11 KO animals. However, the analgesic activity of a number of other opioids with m actions are significantly attenuated or completely lost in the exon 11 KO mice, including levorphanol, butorphanol, buprenorphine, and nalbuphine (Pan et al, 2009;Majumdar et al, 2011bMajumdar et al, , 2012Pasternak and Pan, 2013). Thus, these KO models indicate the existence of two classes of m opioids, the traditional morphinelike ones acting through full-length receptors and atypical ones working through the truncated 6TM splice variants.…”