Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice

Abstract

Our previous results showed that naltrindole (NTI) derivatives with certain types of electron-withdrawing groups as an N-substituent showed δ opioid receptor (DOR) inverse agonistic activities. We therefore synthesized N-acylated NTI derivatives 3a–e and observed that N-benzoyl and N-cyclopropanecarbonyl derivatives SYK-736 (3b) and SYK-623 (3c) were DOR full inverse agonists and the N-acryloyl derivative 3d was a DOR partial inverse agonist. SKY-623 was over 110-fold more potent than the reference compound ICI-174,864. Both naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) derivatives with N-benzoyl and N-cyclopropanecarbonyl groups were also DOR full inverse agonists. These N-acylated inverse agonists are interesting compounds because they have no basic nitrogen atom, which has been demonstrated to be an important pharmacophore. NTI and BNTX-type DOR inverse agonists SYK-623 and SYK-723 (12c) showed dose-dependent antitussive effects in a mouse cough model induced by citric acid exposure. The antitussive effects by SYK-623 and SYK-723 were significantly attenuated by pretreatment with DOR agonist SNC80.

Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives

“…Compound 7 [ 24 , 25 ], which is the key intermediate for the synthesis of the target sulfonamide-type NTI derivatives, was synthesized from naltrexone hydrochloride ( 1 ) ( Scheme 1 ). Fischer indolization of 1 with phenylhydrazine hydrochloride gave NTI ( 2 ) [ 27 , 28 ] in 99% yield, which was treated with acetic anhydride to afford diacetate 3 in 95% yield.…”

“…Among them, compounds 9f and 9g showing high efficacies were almost full inverse agonists. The activity of 9f was comparable to that to SYK-623 (EC 50 = 0.969 nM, E max = −91.2%) [ 25 ]. Interestingly, both compounds possessing the cyclopropyl moiety together with either a C=O or a S=O functionality were inverse agonists, while the NTI-bearing cyclopropylmethyl group, with neither the C=O nor S=O moiety, was a neutral antagonist.…”

“…In the opioid field, since Costa and Herz firstly reported that peptidic ICI-174,864 showed δ opioid receptor (DOR) inverse agonist activity [ 21 ], several peptidic and non-peptidic DOR inverse agonists have been developed [ 4 ]. Possible pharmacological effects resulting from DOR inverse agonism include anorexia [ 22 , 23 ], short-term memory improvement [ 24 ], and antitussive effects [ 25 ]. We also recently reported several DOR inverse agonists with the skeleton of naltrindole (NTI) [ 24 , 25 , 26 ], which was developed as a selective DOR antagonist by Portoghese et al [ 27 , 28 ].…”

“…Interestingly, a series of compounds we reported induced activities from full inverse agonists to full agonists depending on their substituents on the 17-nitrogen atom ( Figure 1 ) [ 24 , 25 , 26 , 29 ]. Amide-type compound SKY-623 bearing 17-cyclopropanecarbonyl group was a DOR full inverse agonist with high potency [ 25 ]. Well-known NTI with the 17-cyclopropylmethyl substituent was a neutral antagonist [ 27 , 28 ].…”

Effects of intracerebroventricularly administered opioid peptide antagonists on tissue glycogen levels in rats after exercise

“…Although there are many studies in the literature on central opioid peptide antagonism and exhausting exercise no other studies have been found on how central antagonism affects glycogen levels in peripheral tissues after exhausting exercise. On the other hand, since NX and NT are also inverse agonists [43,44], the basal activity of endogenous OPR has decreased, thus allowing us to see the effects of OPR on glycogen levels more clearly. However, in order to explain the existing and possible mechanisms in more detail, further studies are needed.…”