Synthesis and Pharmacological Evaluation of SNC80 Analogues with a Bridged Piperazine Ring

Abstract

To discover novel delta-opioid receptor ligands derived from SNC80 (1), a series of 6,8-diazabicyclo[3.2.2]nonane derivatives bearing two aromatic moieties was prepared, and the affinity toward delta, mu, and kappa receptors, as well as sigma receptors, was investigated. After removal of the 4-methoxybenzyl and 2,4-dimethoxybenzyl protecting groups, the pharmacophoric N,N-diethylcarbamoylbenzyl residue was attached to the 6,8-diazabicyclo[3.2.2]nonane framework to yield the designed delta receptor ligands. In a first series of compounds the benzhydryl moiety of SNC80 was dissected, and one phenyl ring was attached to the bicyclic framework. In a second series of delta ligands the complete benzhydryl moiety was introduced into the bicyclic scaffold. The determined delta receptor affinities show that compounds based on an (R)-glutamate-derived bicyclic scaffold possess higher delta receptor affinity than their (S)-glutamate-derived counterparts. Furthermore, an intact benzhydryl moiety leads to delta receptor ligands that are more potent than compounds with two separated aromatic moieties. Compound 24, with the same spatial arrangement of substituents around the benzhydryl stereocenter as SNC80, shows the highest delta receptor affinity of this series: K(i)=24 nM. Whereas the highly potent delta ligands reveal good selectivity against mu and kappa receptors, the sigma(1) and/or sigma(2) affinities of some compounds are almost in the same range as their delta receptor affinities, such as compound 25 (sigma(2): K(i)=83 nM; delta: K(i)=75 nM). In [(35)S]GTPgammaS assays the most potent delta ligands 24 and 25 showed almost the same intrinsic activity as the full agonist SNC80, proving the agonistic activity of 24 and 25. The enantiomeric 4-benzylidene derivatives 15 and ent-15 showed selective cytotoxicity toward the 5637 (bladder) and A-427 (small-cell lung) human tumor cell lines.

Synthesis, pharmacological activity and structure affinity relationships of spirocyclic σ1 receptor ligands with a (2-fluoroethyl) residue in 3-position

“…42 Therefore the affinities of fluspidine 3a towards the phencyclidine binding site of the NMDA receptor 43,44 as well as the opioid receptors (l, j, d receptors) 45,46 were investigated. At a concentration of 1 lM 3a did not compete significantly with the employed radioligands in the NMDA and d assay.…”

Synthesis and Pharmacological Evaluation of 5-Pyrrolidinylquinoxalines as a Novel Class of Peripherally Restricted κ-Opioid Receptor Agonists

“…In the μ assay and the δ assay, [ 3 H]naloxone and [ 3 H]deltorphine served as radioligands, respectively. 35,36 The μ and δ affinity data of the quinoxalines 13−27 are summarized in Table 1.…”

“…The κ receptor affinity of the perhydroquinoxalines 13 – 27 was investigated in a cell-based assay. In this κ assay transfected HEK-293 cell lines expressing the human κ-opioid receptor served as receptor material and [ 3 H]Cl-977 was used as radioligand. , In Table the data recorded with guinea pig brains/[ 3 H]U-69,593 and HEK-293 cells/[ 3 H]Cl-977 are compared.…”

Novel diazabicycloalkane delta opioid agonists

“…23,24 In relation to SNC80 therapeutic potential, several smallmolecule ligands with high affinity and selectivity for d receptors were synthesized in the last decades. [25][26][27][28][29][30] Although the development of SNC80 as first synthetic d agonist drug candidate was interrupted principally for evidences of convulsive effects exerted by its administration, 31 the appearance of these adverse effects have been reviewed 32 and the interest in d opioid agonist development has been recently revamped. [33][34][35][36][37] Particularly, interesting behaviours have been reported in the last years on the selective d opioid agonists KNT-127, 38 ADL5747, 39 AZD2327, 40 and AZD7268 41 (Fig.…”