Opioid Receptor Modulators with a Cinnamyl Group

Ravilla, Lokesh; Naidu, N. Venkata Subba; Dogra, Shalini; Umrao, Deepmala; Yadav, Prem N.; Biswas, Arpita; Michael, Daliah; Sekar, K.; Nagarajan, K.

doi:10.1021/acs.jmedchem.7b00643

Cited by 5 publications

(2 citation statements)

References 31 publications

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“…As shown in Figure 5a, some well-established residue contacts were maintained, including the salt bridge between the pyrrolidine ring nitrogen atom and the D138 3.32 . 35,43 Compared with the model of U69593-κOR complex described by Vardy et al, 36 the binding pattern of pyrrolidine ring of U50,488H was different, but the arylacetamidyl group of our model took a very similar pose in the κOR binding site.…”

Section: Resultsmentioning

confidence: 71%

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

Liu

Jiang

Kong

et al. 2021

ACS Chem. Neurosci.

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κ opioid receptor (κOR) is a subtype of opioid receptors, and there are two major κOR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for κOR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a κOR agonist with a pharmacological profile similar to arylacetamides. Since the recently described morphinan-based compound SLL-039 was identified as a selective and potent κOR agonist that contains a unique benzamidyl substituent in structure similar to arylacetamides, numerous arylacetamidyl substituents were introduced to this scaffold to examine whether the structure−activity relationships (SARs) of arylacetamides in conferring κOR agonistic activities could be reproduced by these analogues. Thus, a series of Ncyclopropylmethyl-7α-arylacetamidylphenyl-6,14-endoethanotetrahydronorthebaine analogues were designed, synthesized, and assayed for biological activities. Among these compounds, compound 4j with a 3′,4′-dimethylphenylacetamidyl substituent showed a single digit low nanomolar affinity to the κOR and relatively high subtype selectivity in binding assays, but this profile was not reproduced in functional assays. In contrast, compound 4i displayed moderately selective κOR agonistic activities in functional assays, which was inconsistent with its nonselective nature in binding assays. Overall, introduction of an arylacetamidyl substituent to the morphinan-based scaffold was associated with pharmacological diversity in both binding and functional activities on opioid receptors in vitro. The resultant SARs were inconsistent with that of classical arylacetamides as κOR agonists, despite bearing a similar arylacetamidyl substituent in the structure. Therefore, the arylacetamidyl substituent of the morphinan-based scaffold was found to be disconnected from that of arylacetamides in conferring κOR activities.

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Section: Resultsmentioning

confidence: 71%

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

Liu

Jiang

Kong

et al. 2021

ACS Chem. Neurosci.

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“…By determining the reaction time (tail withdrawal/flick) of animal's tail to heat, the effectiveness of analgesics or test item is measured. This test was done as described previously with minor modifications [31] . Specifically, hot water bath set at 52±0.5 °C was used as a heat source and mice were individually acclimatized into the restrainers for one minute without tail immersion.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Assessment of Fused β‐Carboline Derivatives as Kappa Opioid Receptor Agonists

et al. 2021

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The synthesis of 5‐formyl‐6‐aryl‐6H‐indolo[3,2,1‐de][1,5] naphthyridine‐2‐carboxylates by reaction between 1‐formyl‐9H‐β‐carbolines and cinnamaldehydes in the presence of pyrrolidine in water with microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused β‐carboline derivatives, which were investigated for their κ‐opioid receptor (KOR) agonistic activity. Two compounds 4 a and 4 c produced appreciable agonist activity on KOR with EC50 values of 46±19 and 134±9 nM, respectively. Moreover, compound‐induced KOR signaling studies suggested both compounds to be extremely G‐protein‐biased agonists. The analgesic effect of 4 a was validated by the increase in tail flick latency in mice in a time‐dependent manner, which was completely blocked by the KOR‐selective antagonist norBNI. Moreover, unlike U50488, an unbiased full KOR agonist, 4 a did not induce sedation. The docking of 4 a with the human KOR was studied to rationalize the result.

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Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents

Ghoshal

Kumar

Yugandhar

et al. 2018

European Journal of Medicinal Chemistry

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Opioid Receptor Modulators with a Cinnamyl Group

Cited by 5 publications

References 31 publications

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

Synthesis and Assessment of Fused β‐Carboline Derivatives as Kappa Opioid Receptor Agonists

Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents

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