Rigid opioids

D-ring modifications most often entail variation of the N- substituent. In this series the pattern of activity is much the same as that in other rigid opioids. Groups such as n-propyl, allyl, dimethylallyl, and CPM afforded antagonists... 

Quantum mechanical calculations have been applied to opioid peptides in attempts to identify low-energy conformers and to study their relationships to rigid opioids. Of the 52 conformations reported for met-enkephalin,(205) the lowest-energy structures (those with AE = 2.5 kcal/mol) were found to have... 

The two /3-turn structures, pc and Pe are the most stable among those considered. This is in accord with the unconstrained nanosecond simulations of linear DPDPE, which converged to these conformers [14]. Because the cyclic form is relatively rigid, it is assumed that the conformation it adopts in solution is the biologically active one, responsible for its high affinity and specificity towards the 5 opioid receptor. The relatively low population of the cyclic-like structure for the linear peptide thus agrees qualitatively with the... 

The multiple conformational restriction of dermorphin-related tet-rapeptide analogues that was performed represents a rational design of opioid peptidomimetics characterized by a high degree of structural rigid-ification. This is indicated by the fact that the p-selective agonist H-Hat-D-Orn-Aic-Glu-NH2 contains only two freely rotatable bonds, whereas there are 14 freely rotatable bonds in [Leu5]enkephalin. 

Morphine generally has sedative effects, reducing overall activity. But local injections into dopaminergic systems can increase locomotor activity, and daily administration can also sensitize one to the locomotor effect (Kalivas and Duffy 1987). High does of opioids create muscle rigidity and catalepsy. 

The use of structurally rigid DKPs as bioactive models for opioid receptor antagonists has been proposed. These compounds are used in the elucidation of the binding requirements and will lead to the design of highly selective molecules with potential clinical application for diseases of the opioid system. These include the treatment of autism, alcohol dependency, and modulation of immunity Further studies by Baures has... 

Opioid-induced muscle rigidity is a frequent complication of this form of anesthesia. It is most common with phenylpiperidine drugs and occurs even after low doses of fentanyl, such as those used in certain diagnostic or minor surgical procedures where a pain-free... 

Muscle rigidity, commonly associated with opioids, seems to be primarily associated with central activation of the p receptor. Rigidity involving the thoracic and abdominal muscles can sometimes interfere with ventilation to such an extent that manual ventilation is... 

The combination of pethidine with monoamine oxidase inhibitors (MAOIs) can cause serious adverse reaction, which can present in two distinct forms. The excitatory form is characterised by sudden agitation, delirium, headache, hypo- or hypertension, rigidity, hyperpyrexia, convulsions and coma. It is thought to be caused by an increase in cerebral 5-HT concentrations because of inhibition of monoamine oxidase. This is potentiated by pethidine, which blocks neuronal uptake of 5-HT. The depressive form, which is frequently severe and fatal, consists of respiratory and cardiovascular depression and coma. It is the result of the inhibition of hepatic microsomal enzymes by the MAOI, leading to accumulation of pethidine. Phenoperidine should also be avoided in patients taking MAOI drugs but other opioids appear to be safe. 

Side-effects The side-effect profile (Poklis, 1995) is typical of potent p-opioids with respiratory depression, increased muscle tone (chest wall rigidity during fentanyl anesthesia), strong sedation and emesis being most prominent. Adverse reactions can be antagonized with naloxone. 

Portoghese and coworkers also considered other naltrindole derivatives substituted in position 6 or 7 with aryl, benzyl or aniline moieties to evaluate the effect of flexible aryl groups on selectivity, but obtained non-selective compounds only. This result demonstrates that the conformational flexibility of these aryl groups causes them to reside preferentially in regions of space that are not accepted by the 8 opioid receptor (Portoghese et al., 1994). A more rigid compound however, 7-benzylidene-naltrindole (BNTX) proved to be a potent and highly... 

Furthermore, high intravenous doses of opioids can cause chest wall rigidity, thereby acutely impairing ventilation, as well as postoperative respiratory depression requiring prolonged assisted ventilation and the administration of opioid antagonists (eg, naloxone). Low doses of fentanyl have been used as premedication and as an adjunct to both intravenous and inhaled anesthetics. 

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