Ananthan Subramaniam, Khare Naveen K, Saini Surendra K, Seitz Lainne E, Bartlett Jeffrey L, Davis Peg, Dersch Christina M, Porreca Frank, Rothman Richard B, Bilsky Edward J
Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama 35255, USA.
J Med Chem. 2004 Mar 11;47(6):1400-12. doi: 10.1021/jm030311v.
A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a-k) were synthesized and evaluated for binding affinity at the opioid delta, micro, and kappa receptors in brain membranes using radioligand binding assays and for functional activity in vitro using [(35)S]GTP-gamma-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) and mouse vas deferens (MVD) smooth muscle preparations. The pyridine ring unsubstituted pyridomorphinans possessing the oxymorphone and hydromorphone framework displayed nearly equal binding affinity at the micro and delta receptors. Their affinities at the kappa site were nearly 10-fold less than their binding affinities at the micro and delta sites. Introduction of aryl substituents at the 5'-position on the pyridine ring improved the binding affinity at the delta site while decreasing the binding affinity at the micro site. Nearly all of the ligands possessing an N-methyl group at the17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed agonist activity at the micro receptor with varying potencies and efficacies. In the [(35)S]GTP-gamma-S binding assays, most of these pyridomorphinans were devoid of any significant agonist activity at the delta and kappa receptors but displayed moderate to potent antagonist activity at the delta receptors. In antinociceptive evaluations using the warm-water tail-withdrawal assay in mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacies when administered by the intracerebroventricular route. Among the ligands studied, the hydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed micro agonist/delta antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard micro agonist morphine produces significant tolerance, repeated administration of the micro agonist/delta antagonist ligand 7h produced no tolerance. These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with mixed micro agonist/delta antagonist profiles and such ligands may have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence, and related side effects.
合成了一系列源自纳洛酮、羟吗啡酮和氢吗啡酮的吡啶吗啡喃类化合物（7a - k），并通过放射性配体结合试验评估其对脑膜中阿片δ、μ和κ受体的结合亲和力，通过在脑组织中进行的[(35)S]GTP - γ - S结合试验以及使用豚鼠回肠（GPI）和小鼠输精管（MVD）平滑肌制备物的生物测定来评估其体外功能活性。具有羟吗啡酮和氢吗啡酮骨架的未被取代的吡啶环吡啶吗啡喃类化合物在μ和δ受体上显示出几乎相等的结合亲和力。它们在κ位点的亲和力比在μ和δ位点的结合亲和力低近10倍。在吡啶环的5'-位引入芳基取代基提高了在δ位点的结合亲和力，同时降低了在μ位点的结合亲和力。几乎所有在吗啡喃部分的17位带有N - 甲基基团且在14位有或没有羟基的配体在μ受体上都表现出激动剂活性，其效力和效能各不相同。在[(35)S]GTP - γ - S结合试验中，这些吡啶吗啡喃类化合物中的大多数在δ和κ受体上没有任何显著的激动剂活性，但在δ受体上表现出中度至强效的拮抗剂活性。在使用小鼠温水甩尾试验的抗伤害感受评估中，当通过脑室内途径给药时，吡啶吗啡喃类化合物产生了效力和效能各不相同的镇痛作用。在所研究的配体中，氢吗啡酮衍生的4 - 氯苯基吡啶吗啡喃7h被鉴定为在体外和体内具有有前景的μ激动剂/δ拮抗剂活性特征的配体。在标准μ激动剂吗啡产生显著耐受性的重复给药范式中，μ激动剂/δ拮抗剂配体7h的重复给药未产生耐受性。这些结果表明，对吗啡喃模板进行适当的分子操作可以提供具有μ激动剂/δ拮抗剂混合特征的配体，并且此类配体可能有潜力成为无耐受性、依赖性和相关副作用的新型镇痛药。
