Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic δ opioid receptor ligands

Xiaoyan Zhang, Kenner C. Rice, Silvia N. Calderon, Hiroshi Kayakiri, Larren Smith, Andrew Coop, Arthur E. Jacobson, Richard B. Rothman, Peg Davis, Christina M. Dersch, Frank Porreca

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

We recently reported (+)-4-[(αR)-α-{(2S,5R)-4-allyl-2,5- dimethyl-1-piperazinyl}-3-methoxybenzyl]-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic δ receptor agonist and explored the structure-activity relationships (SAR) of a series of related derivatives. We have found that δ binding activities and selectivity showed little change when the 3-methoxy group in 1b was removed or replaced by the other substituents, whereas the N,N-diethylbenzamide group is important for interaction with the δ receptor. Extensive modification of the piperazine nucleus led to the synthesis of a new series of N,N-diethyl(α- piperazinylbenzyl)benzamides (2, 3a-e), N,N-diethyl(α- piperidinyl or piperidinylidenebenzyl)benzamides (4a, 5a-c, 6a- b), and related derivatives (4b, 7a-c). Several compounds (2, 3a, 3e, 6a) strongly bound to the δ receptor with K(i) values in the low nanomolar range. On the other hand, the binding affinities of these compounds for the μ and κ receptors were negligible, indicating excellent δ opioid receptor subtype selectivity. The two nitrogen atoms on the piperazine nucleus showed different SAR in the interaction of this series of compounds at the δ receptor. Nitrogen N4 appears to be an important structural element and is essential for electrostatic interaction, while N1 seems to be unnecessary for recognition at the δ receptor.

Original languageEnglish (US)
Pages (from-to)5455-5463
Number of pages9
JournalJournal of Medicinal Chemistry
Volume42
Issue number26
DOIs
StatePublished - Dec 30 1999

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Benzamides
Opioid Receptors
Structure-Activity Relationship
Nitrogen
Ligands
Derivatives
Coulomb interactions
Static Electricity
Atoms
rebemide
piperazine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic δ opioid receptor ligands. / Zhang, Xiaoyan; Rice, Kenner C.; Calderon, Silvia N.; Kayakiri, Hiroshi; Smith, Larren; Coop, Andrew; Jacobson, Arthur E.; Rothman, Richard B.; Davis, Peg; Dersch, Christina M.; Porreca, Frank.

In: Journal of Medicinal Chemistry, Vol. 42, No. 26, 30.12.1999, p. 5455-5463.

Research output: Contribution to journalArticle

Zhang, Xiaoyan ; Rice, Kenner C. ; Calderon, Silvia N. ; Kayakiri, Hiroshi ; Smith, Larren ; Coop, Andrew ; Jacobson, Arthur E. ; Rothman, Richard B. ; Davis, Peg ; Dersch, Christina M. ; Porreca, Frank. / Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic δ opioid receptor ligands. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 26. pp. 5455-5463.
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AU - Smith, Larren

AU - Coop, Andrew

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