morphinans and ketazocine

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

Topics: Acetic Acid; Animals; Benzomorphans; Brain; Dose-Response Relationship, Drug; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Narcotic Antagonists; Pain; Pain Measurement; Reaction Time; Receptors, Opioid, kappa; Receptors, Opioid, mu

Opiate-sensitive feeding behavior has now been demonstrated in a number of species. We sought information on which opioid receptors might be involved in the observed feeding behaviors. Guinea pigs are known to have higher concentrations of the opioid kappa receptor than any other laboratory animal, so we compared the feeding suppressive potency of the general opiate antagonist, diprenorphine to that of the relatively more mu-specific antagonist, naloxone in that species. We found that diprenorphine was over twenty times more effective than naloxone in suppressing feeding in guinea pigs, suggesting the importance of receptors other than mu in feeding initiation in the guinea pig. Confirmatory evidence for the role of kappa receptors was sought, but not found, in comparisons of the effectiveness of different types of opiate agonists in promoting feeding in these animals. These agonists suppressed, rather than stimulated feeding. We conclude that no feeding stimulatory effects of opiates can be demonstrated in guinea pigs. This observation may indicate that opioids play little role in the natural regulation of feeding in this species or that opioids result in prolonged sedation during which the animals fail to eat. The greater feeding suppressive potency of diprenorphine, a general opiate antagonist, versus naloxone, a mu-preferential antagonist, indicates that to whatever extent opiates are involved in guinea pig feeding, the opiate effect is probably not a mu receptor effect.

Topics: Animals; Butorphanol; Circadian Rhythm; Cyclazocine; Diprenorphine; Ethylketocyclazocine; Feeding Behavior; Guinea Pigs; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The hypothesis that the nociceptive state and opiate-induced antinociception are generally regulated by Ca2+ brain levels has been tested. In this context, the effects of intracerebroventricular injections of CaCl2 (0.1-0.5 mumol), D600 (5.0-10.0 micrograms) and EGTA (0.5-1.0 mumol) on ethylketocyclazocine (EKC), ketocyclazocine (KC), Mr-2033, pentazocine (PTC), bremazocine (BMC) and SKF 10,047-induced antinociception were investigated in the mouse tail immersion test. Simultaneous treatment with either D600 or EGTA resulted in a significant and dose-related enhancement in the activities of the kappa-agonists: EKC, KC and Mr-2033, whilst the activities of PTC, BMC and SKF 10,047 remained unchanged. CaCl2 readily blocked the activities of all benzomorphans tested except that of SKF 10,047 against which CaCl2 was less effective. In addition a dose-related hyperalgesia was observed when CaCl2 was given alone. Although the results obtained from the kappa-agonists and CaCl2 per se support the hypothesis in question, data obtained from PTC, BMC and SKF 10,047 tends to oppose it. Additionally the present results taken together indirectly substantiate the notion that benzomorphan-induced analgesia may involve different opiate-sensitive neuronal substrates.

Topics: Analgesia; Analgesics; Analgesics, Opioid; Animals; Benzomorphans; Calcium; Calcium Channel Blockers; Cyclazocine; Egtazic Acid; Ethylketocyclazocine; Gallopamil; Male; Mice; Morphinans; Pentazocine; Phenazocine

The effects of various opioid agonists and antagonists on urination were studied in the normally hydrated rat. Two kappa agonists, U-50,488H and proxorphan, markedly increased urination. The increased urination produced by U-50,488H was antagonized by opioid antagonists in a potency order which indicated that the effects were due to an action at kappa opioid receptors. Mu agonists decreased urination and were blocked by low doses (0.01 and 0.1 mg/kg) of naloxone, whereas kappa agonists increased urination and were only blocked by a high dose (10 mg/kg) of naloxone. The diuretic effects of U-50,488H and ketazocine, but not proxorphan and bremazocine, were reduced by morphine, consistent with the idea that proxorphan and bremazocine have morphine antagonist activity. Water deprivation produced a shift to the right for the dose-effect curve for bremazocine-induced diuresis. Kappa agonists were ineffective in increasing urination in Brattleboro rats that were homozygous for diabetes insipidus, whereas mu agonists were still effective in decreasing urination. The data are consistent with the hypothesis that kappa agonists inhibit release of vasopressin from the neurohypophysis and this decrease in vasopressin release leads to increased urination. The effects of opioids on urination in the normally hydrated rat can be extremely useful in classifying the activities of opioid on mu and kappa receptors in vivo.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Cyclazocine; Diuresis; Ethylketocyclazocine; Male; Morphinans; Naloxone; Narcotic Antagonists; Narcotics; Piperidines; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Urination

Topics: Analgesia; Animals; Benzomorphans; Brain; Cyclazocine; Electric Stimulation; Ethylketocyclazocine; Guinea Pigs; Ileum; Macaca mulatta; Male; Mice; Morphinans; Morphine; Naloxone; Pentazocine; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Vas Deferens

Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.

Topics: Animals; Apomorphine; Cyclazocine; Cyclopropanes; Dextropropoxyphene; Dogs; Ethylketocyclazocine; Humans; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naltrexone; Phenazocine; Spinal Cord