Synthesis and pharmacological evaluation of novel octahydro-1H-pyrido[1,2-a]pyrazine as mu-opioid receptor antagonists.

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Le Bourdonnec B, Goodman AJ, Graczyk TM, Belanger S, Seida PR, DeHaven RN, Dolle RE

Synthesis and pharmacological evaluation of novel octahydro-1H-pyrido[1,2-a]pyrazine as mu-opioid receptor antagonists.

J Med Chem. 2006 Dec 14;49(25):7290-306.

PubMed ID

17149859 [ View in PubMed

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Abstract

To better understand structural requirements for a mu ligand of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class to interact with the mu opioid receptor, we have described in the previous article (Le Bourdonnec, B. et al. J. Med. Chem. 2006, 25, 7278-7289) new, constrained analogues of the N-phenethyl derivative 3. One of the active constrained analogues, compound 4, exhibited subnanomolar mu-opioid receptor affinity (K(i) = 0.62 nM) and potent mu-opioid antagonist activity (IC(50) = 0.54 nM). On the basis of structure 4, a new series of mu-opioid receptor antagonists were designed. In these compounds the octahydroquinolizine template of 4 was replaced by an octahydro-1H-pyrido[1,2-a]pyrazine scaffold. The new derivatives were tested for their binding affinities and in vitro functional activity against the cloned human mu-, delta-, and kappa-opioid receptors. From this study, we identified compound 36, which displays high affinity toward the mu-opioid receptor (K(i) = 0.47 nM), potent mu in vitro antagonist activity (IC(50) = 1.8 nM) and improved binding selectivity profile mu/kappa and mu/delta, when compared to 4.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Naloxone	Kappa-type opioid receptor	Ki (nM)	9.2	N/A	N/A	Details
Naloxone	Mu-type opioid receptor	IC 50 (nM)	7.3	N/A	N/A	Details
Naloxone	Mu-type opioid receptor	Ki (nM)	3.7	N/A	N/A	Details