Opiate rigid

Rigid Geometry Studies of Enkephalin The enkephalins are linear pentapeptides, H-Tyr-Gly-Gly-Phe-Met-NH2 (see Figure 2a.) and H-Tyr-Gly-Gly-Phe-Leu-NH2, which bind to several classes of opiate receptors in the mammalian brain including the same receptor as morphine(26,27). Enkephalins have drawn the interest of theoretical biophysicists for two reasons. First, because of their natural opiate activity, it is hoped that improved analgesics can be developed. Second, as pentapeptides, enkephalins are small enough that the molecule can be examined theoretically without excessive expense of computer time. 

Figure 2. The native Met-enkephalin, NH2-Tyr-Gly-Gly-Phe-Met-OH (a), and the opiate 7-[l-phenyl-3-hydroxyhutyl-3jendotheno-tetrahydrothehaine, PET (b), are shown. The tyramine moiety common to enkephalins and the rigid opiates is circled.

Methano amino acids 6 and 7 (Scheme 6), which have rigidly defined x1 orientations, have been utilized by several groups and shown to induce y-turn structures. Incorporation of (25,35)-c-Met 7 into the anti-opiate peptide H-Phe-Met-Arg-Phe-NH2 (with replacement of the Met residue) using solid-phase synthesis provided an analogue whose lowest energy conformation involved a y-turn centered around the c-Met residue (Scheme 6)J32 ... 

N-(/3-Cyanoethyl)- and N-(y-cyanopropyl)- derivatives of ( )-normetazocine were observed to have good antinociceptive activity in rodents.(46) The NIH(47) group confirmed this and made an extensive study of rigid opiates substituted accordingly. (-)-3-Hydroxy-N-(/3-cyanoethyl) mor-... 

Profound effects on pharmacological activity are exerted when the N-substituent is varied (p 117) These changes in opioid responses parallel those seen in other rigid opiates Groups such as N-allyl, N-CPM, and N-CBM tend to endow the molecule with antagonist properties, whereas N-Me and N-phenethyl are endowed with agonist properties... 

For example, even in the case of "rigid" opiates, it is clear that the flexibility present in the strained, multi-ring structure is significant and cannot be ignored. Even the Ci2"Ci3 bond in morphine (see Figure 1), which forms the nexus of each of the five rings, can be shown to allow a 30° variation within 3 kcal/mole or less, using either experimental or calculated results (79 ). This is an important flexibility that should not... 

Interaction of Model Opiate Anionic Receptor Sites with Characteristic JV-Substituents of Rigid Opiates PCILO and Empirical Potential Energy Calculations... 

The prototypes of rigid opiates all have fused ring structures which may contain three (benzomorphans), four (morphinans), five (morphine) or six (oripavines/thebaines) fused rings. All active opiates in these classes, and in the so-called flexible opiates, exhibit cross tolerance and are reversibly blocked by the opiate antagonist naloxone. 

In this study, as a first step in modeling opiate receptor interactions, we have considered the interaction of an ammonium ion and methyl sulfate or phosphate with the series of compounds shown in Figure 1. These compounds, as N-substitutents in rigid opiates such as 5,9 dimethyl, 2 hydroxy, 6,7 benzomorphans, exhibit a broad spectrum of pharmacological behavior from... 

Expanding this list to other N-substituents and other rigid opiate series increases the correlation, though a number of significant deviations occur (32). 

In this study both the PCILO and empirical energy methods were used to characterize intermolecular interactions of typical N-substituents of rigid opiates with model anionic receptor sites. Ammonium methylphosphate (AMP) and ammonium methylsulfate (AMS) were used as model anionic receptor sites. Interaction energies of eight compounds which, as N-substituents. modulate different antagonist/agonist potencies... 

A series of analogs of the benzomorphans were prepared in which the amino group is exocyclic (99 and 100) (401). In contrast to the benzomorphans and other rigid opiates, the receptor binding of (99) and its analogs exhibits almost no stereoselectivity [K- (jit) = 2.0 and 2.2 nAf for the (+) and (-) isomers] in vivo, both isomers of (99) were inactive. Racemic (100) exhibits an almost 10-fold increase in K-receptor affinity (K = 6.6 nAQ compared to that of the isomers of (99) while retaining nanomolar affinity for ix receptors = 2.0 nM) this compound is a full k agonist in vivo. 

Opiate analgesics may cause rigidity in skeletal muscle. 

Loew, G.H. and Burt, S.K. (1978) Energy conformation study of Met-enkephalin and its D-Ala2 analogue and their resemblance to rigid opiates. Proc. Natl Acad. Sci. USA 75 7-11. 

Fentanyl [437-38-7] (Subhmaze, Leptanal), C22H2gN20, (9) has been extensively used since its introduction into clinical practice in the 1960s (119). Because of its potency, which is 50—100 times that of morphine, a rapid onset of action and a short duration, its use as an iv anesthetic is widespread The short duration results from redistribution from the brain to other tissues, rather than elimination. It does, however, have the usual opiate disadvantages respiratory depression, chest wall rigidity, nausea, and bradycardia. Fentanyl has an extremely wide therapeutic ratio. The size of the dose influences its duration of action which, after iv administration, may last from approximately 30 min to 2 to 3 h (120,121). In cardiac surgery fentanji is administered in very laige doses to produce profound analgesia and suppress cardiovascular reflex responses. This technique is particulady useful for patients with compromised circulation where any increase in cardiac demand could precipitate myocardial ischemia (122). 

Strychnine and tetanus (muscle rigidity) Opiates Phenothlazines and antipsychotic dmgs Sedative-hypnotics Tricyclic antidepressants... 

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