Pharmacological profile of a potent, efficacious fentanyl derivative in rhesus monkeys

The recent synthesis of fentanyl derivatives, some of which appear to have novel profiles of pharmacological effects, has provided compelling evidence that μ opioid efficacy might be altered systematically by modifications in the parent compound fentanyl. In the present study a new 4-(heteroanilido)-piperidine, compound 28, was studied for its effects in rhesus monkeys. In self-administration studies compound 28 maintained rates of lever pressing similar to those maintained by alfentanil; the reinforcing effects of compound 28 were attenuated by the opioid antagonist quadazocine. In drug discrimination studies compound 28 did not substitute for the κ agonist ethylketocyclazocine and did substitute for the μ agonist alfentanil. In morphine-treated subjects discriminating between saline and naltrexone, compound 28 did not substitute for naltrexone; however, in morphine-abstinent subjects compound 28 reversed naltrexone lever responding. Moreover, this discriminative stimulus effect in morphine-abstinent subjects was antagonized by naltrexone and by quadazocine in a manner consistent with μ receptor mediation. Compound 28 also was an effective analgesic in a warm-water, tail-withdrawal procedure and it decreased markedly respiratory function. The analgesic effects as well as the respiratory depressant effects of compound 28 were antagonized by quadazocine. Together, these results show compound 28 to be a potent, efficacious μ agonist of similar potency to alfentanil. Large differences in apparent efficacy at μ receptors between compound 28 and another compound in this series (mirfentanil), clearly demonstrate that, within this chemical family, small chemical changes can confer significant differences in pharmacologic effect.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46340/1/213_2005_Article_BF02245876.pd

Clocinnamox inhibits the intravenous self-administration of opioid agonists in rhesus monkeys: comparison with effects on opioid agonist-mediated antinociception

 The effects of CCAM, an insurmountable mu opioid receptor antagonist, were studied on the intravenous self-administration and thermoantinociception of alfentanil and nalbuphine, high- and low-efficacy opioid agonists, respectively, in rhesus monkeys. A single dose of 0.1 mg/kg CCAM IV reduced alfentanil’s reinforcing potency in an FR30 TO 45s schedule 10-fold within a 24-h period. The maximum response rates remained essentially unchanged. At 1 mg/kg, CCAM caused a 300-fold shift of the alfentanil dose-response curve and also depressed the maximum response rates. CCAM also blocked insurmountably responding for nalbuphine, which was essentially abolished in two of three animals after a dose of 0.1 mg/kg CCAM and in all animals after 1 mg/kg. The acute insurmountable antagonism of alfentanil and nalbuphine self-administration by CCAM was used to determine the (relative initial) efficacy values of both agonists. Efficacy values, tau, were 391 for alfentanil and 196 for nalbuphine; the apparent in vivo dissociation constants, K A , were 0.16 mg/kg per injection (i.e., 350 nmol/kg per injection) for alfentanil and 0.14 mg/kg (370 nmol/kg per injection) for nalbuphine. In comparison, in a rhesus monkey 50°C warm-water tail withdrawal assay, the tau values were 11 for alfentanil and 0.92 for nalbuphine, and the K A values were 0.2 mg/kg (440 nmol/kg) for alfentanil and 0.15 mg/kg (400 nmol/kg) for nalbuphine. Therefore, it seems that the higher potency of alfentanil and nalbuphine in self-administration as compared to thermal antinociception in rhesus monkeys is predominantly due to a larger efficacy of the same agonist in self-administration (i.e., a larger receptor pool) rather than differences in apparent in vivo affinity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41957/1/213-129-3-233_71290233.pd