The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and ß-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects.
Psychopharmacology (Berl)
; 234(16): 2499-2514, 2017 Aug.
Article
em En
| MEDLINE
| ID: mdl-28536865
ABSTRACT
RATIONALE Kappa-opioid receptor (KOPr) agonists have pre-clinical anti-cocaine and analgesic effects. However, side effects including sedation, dysphoria, aversion, anxiety and depression limit their therapeutic development. The unique structure of salvinorin A has been used to develop longer acting KOPr agonists. OBJECTIVES:
We evaluate two novel C-2 analogues of salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and ß-tetrahydropyran Sal B (ß-THP Sal B) alongside U50,488 for their ability to modulate cocaine-induced behaviours and side effects, pre-clinically.METHODS:
Anti-cocaine properties of EOM Sal B were evaluated using the reinstatement model of drug seeking in self-administering rats. EOM Sal B and ß-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and ß-THP Sal B were evaluated for aversive, anxiogenic and depressive-like effects using conditioned place aversion (CPA), elevated plus maze (EPM) and forced swim tests (FSTs), respectively.RESULTS:
EOM Sal B (0.1, 0.3 mg/kg, intraperitoneally (i.p.)) dose dependently attenuated drug seeking, and EOM Sal B (0.1 mg/kg, i.p.) and ß-THP Sal B (1 mg/kg, i.p.) attenuated cocaine-induced hyperactivity. No effects on locomotor activity, open arm times (EPM) or swimming behaviours (FST) were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or ß-THP Sal B (1 or 2 mg/kg, i.p.). However, ß-THP Sal B decreased time spent in the drug-paired chamber.CONCLUSION:
EOM Sal B is more potent than Sal A and ß-THP Sal B in reducing drug-seeking behaviour with fewer side effects. EOM Sal B showed no effects on sucrose self-administration (0.1 mg/kg), locomotor, depressive-like, aversive-like or anxiolytic effects.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Aprendizagem da Esquiva
/
Cocaína
/
Diterpenos Clerodânicos
/
Comportamento de Procura de Droga
/
Atividade Motora
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article