TY - JOUR
T1 - δ-Opioid Agonists
T2 - Differential Efficacy and Potency of SNC80, Its 3-OH (SNC86) and 3-Desoxy (SNC162) Derivatives in Sprague-Dawley Rats
AU - Jutkiewicz, Emily M.
AU - Eller, Erik B.
AU - Folk, John E.
AU - Rice, Kenner C.
AU - Traynor, John R.
AU - Woods, James H.
PY - 2004/4
Y1 - 2004/4
N2 - The diarylpiperazine δ-opioid agonist SNC80 [(+)-4-[(α R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl) methyl]-N,N-diethylbenzamide] produces convulsions, antidepressant-like effects, and locomotor stimulation in rats. The present study compared the behavioral effects in Sprague-Dawley rats of SNC80 with its two derivatives, SNC86 [(+)-4-[α(R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl] -(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] and SNC162 [(+)-4-[(α R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl] -N,N-diethylbenzamide], which differ by one functional group located in the 3-position of the benzylic ring. In behavioral measures, these three compounds demonstrated a rank order of potency and efficacy; SNC86 was the most potent and efficacious followed by SNC80 and then SNC162. In vitro, these compounds stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([ 35S]GTPγS) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [ 35S]GTPγS binding studies, SNC86 seemed to be a full agonist at the δ-opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [35S]GTPγS autoradiography studies, it produced behavioral effects similar to those observed with SNC86, suggesting that the behavioral effects of SNC80 may be produced by its 3-hydroxy metabolite.
AB - The diarylpiperazine δ-opioid agonist SNC80 [(+)-4-[(α R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl) methyl]-N,N-diethylbenzamide] produces convulsions, antidepressant-like effects, and locomotor stimulation in rats. The present study compared the behavioral effects in Sprague-Dawley rats of SNC80 with its two derivatives, SNC86 [(+)-4-[α(R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl] -(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] and SNC162 [(+)-4-[(α R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl] -N,N-diethylbenzamide], which differ by one functional group located in the 3-position of the benzylic ring. In behavioral measures, these three compounds demonstrated a rank order of potency and efficacy; SNC86 was the most potent and efficacious followed by SNC80 and then SNC162. In vitro, these compounds stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([ 35S]GTPγS) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [ 35S]GTPγS binding studies, SNC86 seemed to be a full agonist at the δ-opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [35S]GTPγS autoradiography studies, it produced behavioral effects similar to those observed with SNC86, suggesting that the behavioral effects of SNC80 may be produced by its 3-hydroxy metabolite.
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U2 - 10.1124/jpet.103.061242
DO - 10.1124/jpet.103.061242
M3 - Article
C2 - 14722329
AN - SCOPUS:1642390536
VL - 309
SP - 173
EP - 181
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 1
ER -