Hammilton
04-24-2007, 02:53 PM
you guys ever check out what sorts of morphine-derivatives there are out there that are full agonists (or even agonist-antagonists?)???? It's fucking nuts
carbamates are mostly insecticides as i'm sure our chemists know, but there are more than a few used as meds.
Phenprobamate, meprobamate, Mebutamate, Cyclarbamate, etc. I think those were were entirely drugs, no insecticides (i'd hate to fuck that up).
Phenprobamate is quite a bit like meprobamate, and unscheduled (analogue?), but I wonder if there is a Carisoprodol-->Meprobamate, XXXXX ---> Phenprobamate. Since Carisoprodol isn't scheduled, there's no way the "carisoprodol to phenprobamate" would be.
-------------------------
that had nothing to do with this, though. Still, I think most of us here love depressants in general (I like most except alcohol, but i've got love for the benzos, but not a lot). Some of these citations aren't relevant, but still interesting to me.
This is what I was posting about:
High-affinity carbamate analogues of morphinan at opioid receptors.
Peng X (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Peng+X%22%5BAuthor%5D),
Knapp BI (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Knapp+BI%22%5BAuthor%5D),
Bidlack JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Bidlack+JM%22%5BAuthor%5D),
Neumeyer JL (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Neumeyer+JL%22%5BAuthor%5D). Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
A series of carbamate analogues were synthesized from levorphanol (1a), cyclorphan (2a) or butorphan (3a) and evaluated in vitro for their binding affinity at mu, delta, and kappa opioid receptors. Functional activities of these compounds were measured in the [(35)S]GTPgammaS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for kappa receptor (K(i)=0.046 and 0.051 nM) and for mu receptor (K(i)=0.11 and 0.12 nM). Compound 1c showed the highest mu selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [(35)S]GTPgammaS binding mediated by the kappa opioid receptor illustrated that all of these ligands were kappa agonists. At the mu receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c-e and 3c-e were mu agonists/antagonists.
PMID: 17276685 [PubMed - in process]
----------------------------------------
there's a lot more of this stuff (in line with my previous PEA-morphinan analogues post)- unscheduled morphine derivatives that are borne out of unscheduled parent compounds.
In-vitro investigation of oxazol and urea analogues of morphinan at opioid receptors.
Peng X (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Peng+X%22%5BAuthor%5D),
Knapp BI (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Knapp+BI%22%5BAuthor%5D),
Bidlack JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Bidlack+JM%22%5BAuthor%5D),
Neumeyer JL (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Neumeyer+JL%22%5BAuthor%5D). Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
A series of 2-amino-oxazole (7 and 8) analogs and 2-one-oxazole analogs (9 and 10) were synthesized from cyclorphan (1) or butorphan (2) and evaluated in-vitro by their binding affinity at mu, delta, and kappa opioid receptors and compared with their 2-aminothiozole analogs 5 and 6. Ligands 7-10 showed decreased affinities at kappa and mu receptors. Urea analogs (11-14) were also prepared from 2-aminocyclorphan (3) or 2-aminobutorphan (4) and evaluated in-vitro by their binding affinity at mu, delta, and kappa opioid receptors. The urea derived opioids retained their affinities at mu receptors while showing increased affinities at delta receptors and decreased affinities at kappa receptors. Functional activities of these compounds were measured in the [(35)S]GTPgammaS binding assay, illustrating that all of these ligands were kappa agonists. At the mu receptor, compounds 11 and 12 were mu agonist/antagonists.
PMID: 17433695 [PubMed - as supplied by publisher]
Synthesis and in vitro evaluation of iodinated derivatives of piperazine as a new ligand for sigma receptor imaging by single photon emission computed tomography.
Hirata M (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Hirata+M%22%5BAuthor%5D),
Mori T (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Mori+T%22%5BAuthor%5D),
Soga S (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Soga+S%22%5BAuthor%5D),
Umeda T (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Umeda+T%22%5BAuthor%5D),
Ohmomo Y (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Ohmomo+Y%22%5BAuthor%5D). Osaka University of Pharmaceutical Sciences, Japan.
A new series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) was synthesized and evaluated as a potential brain sigma-1 receptor imaging ligands by single photon emission computed tomography (SPECT). Iodinated analogues of SA4503 (4a-c) were prepared from piperazine in a high yield. The in vitro competition binding studies using [3H] DTG (sigma-1, 2), [3H] (+)-pentazocine (sigma-1), and [3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC50: 4a=7.1, 4b=31.0, and 4c=77.3 nM). In particular, the affinity of 4a, bearing iodine at ortho position on the phenyl ring, was 4.4 times greater than SA4503, and 3 times greater than that of haloperidol. The meta-iodo analogue 4b was the same to SA4503, the lead compound. The radioiodinated derivatives, [125I] 4a, 4b were synthesized no-carrier-added from the corresponding tributyltin precursors by the iododestannylation reaction with high yields. The binding of [125I] 4a, 4b have been characterized in the rat brain membranes. These compounds were indicated single population binding to sigma receptor with high affinity (4a: Kd=1.86+/-0.34 nM, Bmax=205+/-28.9 fmol/mg protein, 4b: Kd=3.30+/-0.51 nM, Bmax=231.5+/-13.8 fmol/mg protein). In vitro blocking studies were confirmed that the high specificity of 4a, 4b. These results suggest that radioiodinated 4a and 4b are promising sigma receptors imaging ligand for pursuing further in vivo studies.
PMID: 16595947 [PubMed - indexed for MEDLINE]
Structural determinants of opioid activity in derivatives of 14-aminomorphinones: effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones.
Nieland NP (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Nieland+NP%22%5BAuthor%5D),
Moynihan HA (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Moynihan+HA%22%5BAuthor%5D),
Carrington S (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Carrington+S%22%5BAuthor%5D),
Broadbear J (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Broadbear+J%22%5BAuthor%5D),
Woods JH (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Woods+JH%22%5BAuthor%5D),
Traynor JR (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Traynor+JR%22%5BAuthor%5D),
Husbands SM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Husbands+SM%22%5BAuthor%5D),
Lewis JW (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Lewis+JW%22%5BAuthor%5D). School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the 2' and 4' positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be observed where the 2'-chloro and 2'-methyl ligands consistently displayed higher efficacy than their 4'-substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have greater efficacy at the mu opioid receptor than their 17-cyclopropylmethyl counterparts.
PMID: 16913723 [PubMed - indexed for MEDLINE]
Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronide.
Macdougall JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Macdougall+JM%22%5BAuthor%5D),
Zhang XD (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Zhang+XD%22%5BAuthor%5D),
Polgar WE (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Polgar+WE%22%5BAuthor%5D),
Khroyan TV (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Khroyan+TV%22%5BAuthor%5D),
Toll L (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Toll+L%22%5BAuthor%5D),
Cashman JR (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Cashman+JR%22%5BAuthor%5D). Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, USA. jmacdougall@hbri.org
A series of 6-beta-arylamidomorphines was synthesized and biologically evaluated. Various aryl substituents were introduced into the arylamidomorphines to examine substituent structure-activity relationships. Competition binding assays showed that compounds 10a-h bound to the mu opioid receptor with high affinity (0.2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat.
PMID: 15498674 [PubMed - indexed for MEDLINE]
Design, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronide.
MacDougall JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22MacDougall+JM%22%5BAuthor%5D),
Zhang XD (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Zhang+XD%22%5BAuthor%5D),
Polgar WE (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Polgar+WE%22%5BAuthor%5D),
Khroyan TV (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Khroyan+TV%22%5BAuthor%5D),
Toll L (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Toll+L%22%5BAuthor%5D),
Cashman JR (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Cashman+JR%22%5BAuthor%5D). Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, USA.
A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive binding assays at mu, delta, and kappa opioid receptors. The thiosaccharide compounds in the morphine series 5b, 5e, 6a, and 6c showed 1.5-2.4-fold higher affinity for the mu receptor than M6G, but were generally less selective than M6G. The functional activity of the M6G and C6G analogues was examined with the [35S]GTP-gamma-S assay. Compounds 5b and 5e were determined to be full mu agonists, whereas compounds 6a and 6c were partial mu agonists. The in vivo antinociceptive activity of compound 5b was evaluated by the tail flick latency test, giving an ED50 of 2.5 mg/kg.
PMID: 15509180 [PubMed - indexed for MEDLINE]
The orvinols and related opioids--high affinity ligands with diverse efficacy profiles.
Lewis JW (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Lewis+JW%22%5BAuthor%5D),
Husbands SM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Husbands+SM%22%5BAuthor%5D). Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK. prxjwl@bath.ac.uk
The thevinols and orvinols derived from thebaine via the thebaine-methylvinyl ketone adduct (thevinone) were thoroughly investigated in the 1960's and 1970's by the Reckitt group. From this work a number of important opioids emerged. Buprenorphine is a mu partial agonist, kappa/delta-antagonist that is now used primarily in the treatment of heroin abuse and dependence though it was initially launched as an analgesic for the treatment of moderate to severe pain. Etorphine and dihydroetorphine are very potent mu agonists that have found application in veterinary and human medicine respectively. Diprenorphine is primarily a mu antagonist though it also has some kappa-partial agonist effects. It has high affinity for all types of opioid receptors and as a "universal" opioid ligand has been much in demand as a pharmacological tool. It has also been converted into a [11C] version for use in Positron Emission Tomography (PET) studies of brain function related to the opioid receptor system. More recent medicinal chemistry investigations have been concerned with gaining a greater understanding of buprenorphine's unique opioid profile. This has involved the synthesis and evaluation of a number of series of buprenorphine analogues in which the C20 t-butyl group has been constrained in a ring system. These studies have suggested that the methyls in the t-butyl group inhibit the conformational changes in the kappa-receptor required for generation of an agonist response. Introduction of a 7alpha-cinnamoylaminomethyl group in place of the orvinol tertiary alcohol function leads to selective irreversible mu antagonism.
carbamates are mostly insecticides as i'm sure our chemists know, but there are more than a few used as meds.
Phenprobamate, meprobamate, Mebutamate, Cyclarbamate, etc. I think those were were entirely drugs, no insecticides (i'd hate to fuck that up).
Phenprobamate is quite a bit like meprobamate, and unscheduled (analogue?), but I wonder if there is a Carisoprodol-->Meprobamate, XXXXX ---> Phenprobamate. Since Carisoprodol isn't scheduled, there's no way the "carisoprodol to phenprobamate" would be.
-------------------------
that had nothing to do with this, though. Still, I think most of us here love depressants in general (I like most except alcohol, but i've got love for the benzos, but not a lot). Some of these citations aren't relevant, but still interesting to me.
This is what I was posting about:
High-affinity carbamate analogues of morphinan at opioid receptors.
Peng X (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Peng+X%22%5BAuthor%5D),
Knapp BI (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Knapp+BI%22%5BAuthor%5D),
Bidlack JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Bidlack+JM%22%5BAuthor%5D),
Neumeyer JL (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Neumeyer+JL%22%5BAuthor%5D). Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
A series of carbamate analogues were synthesized from levorphanol (1a), cyclorphan (2a) or butorphan (3a) and evaluated in vitro for their binding affinity at mu, delta, and kappa opioid receptors. Functional activities of these compounds were measured in the [(35)S]GTPgammaS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for kappa receptor (K(i)=0.046 and 0.051 nM) and for mu receptor (K(i)=0.11 and 0.12 nM). Compound 1c showed the highest mu selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [(35)S]GTPgammaS binding mediated by the kappa opioid receptor illustrated that all of these ligands were kappa agonists. At the mu receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c-e and 3c-e were mu agonists/antagonists.
PMID: 17276685 [PubMed - in process]
----------------------------------------
there's a lot more of this stuff (in line with my previous PEA-morphinan analogues post)- unscheduled morphine derivatives that are borne out of unscheduled parent compounds.
In-vitro investigation of oxazol and urea analogues of morphinan at opioid receptors.
Peng X (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Peng+X%22%5BAuthor%5D),
Knapp BI (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Knapp+BI%22%5BAuthor%5D),
Bidlack JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Bidlack+JM%22%5BAuthor%5D),
Neumeyer JL (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Neumeyer+JL%22%5BAuthor%5D). Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
A series of 2-amino-oxazole (7 and 8) analogs and 2-one-oxazole analogs (9 and 10) were synthesized from cyclorphan (1) or butorphan (2) and evaluated in-vitro by their binding affinity at mu, delta, and kappa opioid receptors and compared with their 2-aminothiozole analogs 5 and 6. Ligands 7-10 showed decreased affinities at kappa and mu receptors. Urea analogs (11-14) were also prepared from 2-aminocyclorphan (3) or 2-aminobutorphan (4) and evaluated in-vitro by their binding affinity at mu, delta, and kappa opioid receptors. The urea derived opioids retained their affinities at mu receptors while showing increased affinities at delta receptors and decreased affinities at kappa receptors. Functional activities of these compounds were measured in the [(35)S]GTPgammaS binding assay, illustrating that all of these ligands were kappa agonists. At the mu receptor, compounds 11 and 12 were mu agonist/antagonists.
PMID: 17433695 [PubMed - as supplied by publisher]
Synthesis and in vitro evaluation of iodinated derivatives of piperazine as a new ligand for sigma receptor imaging by single photon emission computed tomography.
Hirata M (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Hirata+M%22%5BAuthor%5D),
Mori T (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Mori+T%22%5BAuthor%5D),
Soga S (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Soga+S%22%5BAuthor%5D),
Umeda T (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Umeda+T%22%5BAuthor%5D),
Ohmomo Y (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Ohmomo+Y%22%5BAuthor%5D). Osaka University of Pharmaceutical Sciences, Japan.
A new series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) was synthesized and evaluated as a potential brain sigma-1 receptor imaging ligands by single photon emission computed tomography (SPECT). Iodinated analogues of SA4503 (4a-c) were prepared from piperazine in a high yield. The in vitro competition binding studies using [3H] DTG (sigma-1, 2), [3H] (+)-pentazocine (sigma-1), and [3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC50: 4a=7.1, 4b=31.0, and 4c=77.3 nM). In particular, the affinity of 4a, bearing iodine at ortho position on the phenyl ring, was 4.4 times greater than SA4503, and 3 times greater than that of haloperidol. The meta-iodo analogue 4b was the same to SA4503, the lead compound. The radioiodinated derivatives, [125I] 4a, 4b were synthesized no-carrier-added from the corresponding tributyltin precursors by the iododestannylation reaction with high yields. The binding of [125I] 4a, 4b have been characterized in the rat brain membranes. These compounds were indicated single population binding to sigma receptor with high affinity (4a: Kd=1.86+/-0.34 nM, Bmax=205+/-28.9 fmol/mg protein, 4b: Kd=3.30+/-0.51 nM, Bmax=231.5+/-13.8 fmol/mg protein). In vitro blocking studies were confirmed that the high specificity of 4a, 4b. These results suggest that radioiodinated 4a and 4b are promising sigma receptors imaging ligand for pursuing further in vivo studies.
PMID: 16595947 [PubMed - indexed for MEDLINE]
Structural determinants of opioid activity in derivatives of 14-aminomorphinones: effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones.
Nieland NP (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Nieland+NP%22%5BAuthor%5D),
Moynihan HA (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Moynihan+HA%22%5BAuthor%5D),
Carrington S (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Carrington+S%22%5BAuthor%5D),
Broadbear J (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Broadbear+J%22%5BAuthor%5D),
Woods JH (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Woods+JH%22%5BAuthor%5D),
Traynor JR (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Traynor+JR%22%5BAuthor%5D),
Husbands SM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Husbands+SM%22%5BAuthor%5D),
Lewis JW (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Lewis+JW%22%5BAuthor%5D). School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the 2' and 4' positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be observed where the 2'-chloro and 2'-methyl ligands consistently displayed higher efficacy than their 4'-substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have greater efficacy at the mu opioid receptor than their 17-cyclopropylmethyl counterparts.
PMID: 16913723 [PubMed - indexed for MEDLINE]
Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronide.
Macdougall JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Macdougall+JM%22%5BAuthor%5D),
Zhang XD (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Zhang+XD%22%5BAuthor%5D),
Polgar WE (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Polgar+WE%22%5BAuthor%5D),
Khroyan TV (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Khroyan+TV%22%5BAuthor%5D),
Toll L (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Toll+L%22%5BAuthor%5D),
Cashman JR (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Cashman+JR%22%5BAuthor%5D). Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, USA. jmacdougall@hbri.org
A series of 6-beta-arylamidomorphines was synthesized and biologically evaluated. Various aryl substituents were introduced into the arylamidomorphines to examine substituent structure-activity relationships. Competition binding assays showed that compounds 10a-h bound to the mu opioid receptor with high affinity (0.2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat.
PMID: 15498674 [PubMed - indexed for MEDLINE]
Design, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronide.
MacDougall JM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22MacDougall+JM%22%5BAuthor%5D),
Zhang XD (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Zhang+XD%22%5BAuthor%5D),
Polgar WE (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Polgar+WE%22%5BAuthor%5D),
Khroyan TV (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Khroyan+TV%22%5BAuthor%5D),
Toll L (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Toll+L%22%5BAuthor%5D),
Cashman JR (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Cashman+JR%22%5BAuthor%5D). Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, USA.
A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive binding assays at mu, delta, and kappa opioid receptors. The thiosaccharide compounds in the morphine series 5b, 5e, 6a, and 6c showed 1.5-2.4-fold higher affinity for the mu receptor than M6G, but were generally less selective than M6G. The functional activity of the M6G and C6G analogues was examined with the [35S]GTP-gamma-S assay. Compounds 5b and 5e were determined to be full mu agonists, whereas compounds 6a and 6c were partial mu agonists. The in vivo antinociceptive activity of compound 5b was evaluated by the tail flick latency test, giving an ED50 of 2.5 mg/kg.
PMID: 15509180 [PubMed - indexed for MEDLINE]
The orvinols and related opioids--high affinity ligands with diverse efficacy profiles.
Lewis JW (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Lewis+JW%22%5BAuthor%5D),
Husbands SM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Husbands+SM%22%5BAuthor%5D). Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK. prxjwl@bath.ac.uk
The thevinols and orvinols derived from thebaine via the thebaine-methylvinyl ketone adduct (thevinone) were thoroughly investigated in the 1960's and 1970's by the Reckitt group. From this work a number of important opioids emerged. Buprenorphine is a mu partial agonist, kappa/delta-antagonist that is now used primarily in the treatment of heroin abuse and dependence though it was initially launched as an analgesic for the treatment of moderate to severe pain. Etorphine and dihydroetorphine are very potent mu agonists that have found application in veterinary and human medicine respectively. Diprenorphine is primarily a mu antagonist though it also has some kappa-partial agonist effects. It has high affinity for all types of opioid receptors and as a "universal" opioid ligand has been much in demand as a pharmacological tool. It has also been converted into a [11C] version for use in Positron Emission Tomography (PET) studies of brain function related to the opioid receptor system. More recent medicinal chemistry investigations have been concerned with gaining a greater understanding of buprenorphine's unique opioid profile. This has involved the synthesis and evaluation of a number of series of buprenorphine analogues in which the C20 t-butyl group has been constrained in a ring system. These studies have suggested that the methyls in the t-butyl group inhibit the conformational changes in the kappa-receptor required for generation of an agonist response. Introduction of a 7alpha-cinnamoylaminomethyl group in place of the orvinol tertiary alcohol function leads to selective irreversible mu antagonism.