Maruf Ahmed

Identification of binding sites of prazosin, tamsulosin and KMD-3213 with α1-adrenergic receptor subtypes by molecular modeling

This investigation was performed to assess the importance of interaction in the bindings of selective and nonselective alpha(1)-antagonists to alpha(1)-adrenergic receptor (alpha(1)-AR) subtypes using molecular modeling. The alpha(1)-antagonists used in this study were prazosin, tamsulosin and KMD-3213. Molecular modeling was performed on Octane 2 workstation (Silicon Graphics) using Discover/Insight II software (Molecular Simulations Inc.). Through molecular modeling, possible binding sites for these drugs were suggested to lie between transmembrane domains (TM) 3, 4, 5 and 6 of the alpha(1)-AR subtypes. In prazosin, the 4-amino group, 1-nitrogen atom and two methoxy groups of quinazoline ring possibly interact with the amino acids in TM3, TM5 and TM6 of alpha(1)-ARs. In tamsulosin, amine group of ethanyl amine chain, methoxy group of benzene ring and sulfonamide nitrogen of benzene ring interacts in TM3, TM4 and TM5 of alpha(1)-ARs. In KMD-3213, amine of ethyl amine chain and indoline nitrogen of this compound possibly interact within TM3 and TM5 of alpha(1)-ARs. Amide nitrogen of KMD-3213 also interacts within TM4 of alpha(1A)-AR. The results of the present study suggested that prazosin has similar binding sites in all the alpha(1)-AR subtypes while tamsulosin interacts at higher number of sites with alpha(1D)-subtype than other alpha(1)-AR subtypes. KMD-3213 being an alpha(1A)-AR selective ligand, binds to higher number of sites of alpha(1A) subtype than to other subtypes. All these amino acids are located near the extracellular loop. These findings are consistent with the previous studies that antagonists bind higher in the pocket closer to the extracellular surface unlike agonist binding.

Binding and functional affinity of some newly synthesized phenethylamine and phenoxypropanolamine derivatives for their agonistic activity at recombinant human β3‐adrenoceptor

β3‐Adrenoceptor is the predominant β‐adrenoceptor in adipocytes and has drawn much attention during the investigation for anti‐obesity and antidiabetes therapeutics. Thirteen new compounds have been evaluated for their potencies and efficacies as β3‐adrenoceptor agonists on human β3‐ adrenoceptor expressed in COS‐7 and Chinese hamster ovary (CHO) cells using radio ligand binding assay and cyclic AMP (cAMP) accumulation assay. Phenoxypropanolamine derivatives, SWR‐0334NA (([E)‐[4‐[5‐[(3‐phenoxy‐2‐hydroxypropyl)amino]‐2‐pentene−3‐yl] phenoxy]acetic acid sodium salt), SWR‐0335SA ((E)‐[4‐[5‐[(3‐phenoxy‐2‐hydroxypropyl)amino]‐2‐pentene−3‐yl] phenoxy] acetic acid ethanedioic acid), SWR‐0342SA (S‐(Z)‐[4‐[[1‐[2‐[(2‐hydroxy−3‐phenoxypropyl)]amino]ethyl]‐1‐pro‐penyl]phenoxy] acetic acid ethanedioic acid), SWR‐0348SA‐SITA ((E)‐[4‐[5‐[(3‐phenoxy‐2‐hydroxy‐propyl)amino]‐2‐hexene−3‐yl] phenoxy]acetic acid ethanedioic acid) and SWR‐0361SA ((E)‐N‐methyl‐[4‐[5‐[(3‐phenoxy‐2‐hydroxypropyl)amino]‐2‐pentene−3‐yl]phenoxy]acetoamide ethanedioic acid) showed higher agonistic activity for the β3‐adrenoceptor. Among the compounds tested, SWR‐0334NA exhibited full agonist activity (%Emax = 100.26) despite its lower binding affinity (pK1 = 6.11). Compounds SWR‐0338SA((E)‐[4‐[5‐[(2‐phenyl‐2‐hydroxyethyl)amino]‐2‐pentene−3‐yl]phenoxy]acetic acid ethanedioic acid), SWR‐0339SA (S‐(E)‐[4‐[5‐[(3‐phenoxy‐2‐hydroxypropyl)amino]‐2‐pentene−3‐yl] phenoxy] acetic acid ethanedioic acid), SWR‐0345HA ((E)‐2‐methyl−3‐[4‐[2‐(2‐phenyl‐2‐hydroxyethyl‐amino)ethoxy] phenyl]‐2‐propenoic acid ethyl ester hydrochloride), SWR‐0358SA ((E)‐(2‐methoxy‐ethyl)‐[4‐[5‐[(3‐phenoxy‐2‐hydroxypropyl) amino]‐2‐pentene−3‐yl]phenoxy]acetoamide ethanedioic acid) and SWR‐0362SA ((E)‐1‐[[[4‐[5‐[(3‐phenoxy‐2‐hydroxypropyl)amino]‐2‐pentene −3‐yl]phenoxy]‐acetyl]carbonyl]piperidine ethanedioic acid) had moderate agonistic activity and were phenethylamine and phenoxypropanolamine derivatives. Compounds SWR‐0065HA ([4‐[2‐[3‐[[(3,4‐dihydro‐4‐oxo‐[1,2,4]‐triazino(4,5‐a)indol)‐lyl]oxy]‐2‐hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR‐0098NA ((E)‐[4‐[3‐[(2‐phenyl‐2‐hydroxyethyl)amino]‐1‐butenyl] phenoxy]‐acetic acid sodium salt) and SWR‐0302HA ([4‐[[4‐[2‐(3‐chlorophenoxy‐2‐hydroxypropyl)amino]‐E‐2‐butenyl]oxy]phenoxy]acetic acid hydrochloride) had very low binding affinity towards β3‐adreno‐ceptors and they did not induce cAMP accumulation. We concluded that compounds SWR‐0334NA, SWR‐0335SA, SWR‐0342SA, SWR‐0348SA‐SITA and SWR‐0361SA were potential agonists of human β3‐ adrenoceptor. Further investigation on their selectivity towards β3‐adrenoceptor could be useful for the exploration of the physiological properties of the β3‐adrenoceptor.

Comparison of the binding affinity of some newly synthesized phenylethanolamine and phenoxypropanolamine compounds at recombinant human β‐ and α1‐adrenoceptor subtypes

We evaluated six new compounds, SWR‐0065HA ([4‐[2‐[3‐[[(3,4‐dihydro‐4‐oxo‐[1,2,4]‐triazino(4,5‐a)indol)‐lyl]oxy]‐2‐hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR‐0098NA ((R*R*‐UE)‐(E)‐[4‐[3‐[(2‐phenyl‐2‐hydroxyethyl)amino]‐1‐butenyl]phenoxy]acetic acid sodium salt), SWR‐0315NA ((E, Z)‐[4[[1‐[2‐[(3‐phenoxy‐2‐hydroxy propyl)]amino]ethyl]‐1‐propenyl]phenoxy]acetic acid sodium), SWR‐0338SA ((E)‐[4‐[5‐[(2‐phenyl‐2‐hydroxyethyl)amino]‐2‐pentene‐3‐yl]phenoxy] acetic acid ethanedioic acid), SWR‐0342SA ((S)‐(Z)‐[4‐[[1‐[2‐[(2‐hydroxy‐3‐phenoxypropyl)]amino] ethyl]‐1‐propenyl]phenoxy]acetic acid ethanedioic acid) and SWR‐0345HA ((E)‐2‐methyl‐3‐[4‐[2‐(2‐phenyl‐2‐hydroxyethylamino)ethoxy]phenyl]‐2‐propenoic acid ethyl ester hydrochloride) for their potencies as selective ligands at human β‐adrenoceptors expressed in COS‐7 cells and compared the binding affinities for human α1‐adrenoceptors expressed in Chinese hamster ovary (CHO) cells using a radioligand‐binding assay. Phenoxypropanolamine derivatives SWR‐0315NA and SWR‐0342SA showed higher binding affinities for β‐adrenoceptor subtypes; SWR‐0065HA, however, showed a higher affinity for only β2‐adrenoceptors, accounting for 3‐fold and 6‐fold selectivity against β1‐ and β3‐adrenoceptors. Compounds SWR‐0315NA and SWR‐0342SA did not show any binding selectivity for any of the subtypes. However, functionally these two compounds are selective for β3‐adrenoceptors. Among the phenylethanolamine derivatives, SWR‐0338SA and SWR‐0345HA showed 9‐fold and 16‐fold higher binding selectivity for β3‐adrenoceptors against β1‐adrenoceptors, respectively, whereas they both showed a 7‐fold higher binding selectivity for β3‐adrenoceptors against β2‐adrenoceptors. SWR‐0098NA did not show any significant binding affinity for any of the β‐adrenoceptor subtypes. These compounds, except for SWR‐0098NA, were not found to possess any significant binding affinity for α1‐adrenoceptor subtypes over that for β‐adrenoceptor subtypes. However, SWR‐0098NA has about a 3‐fold to 22‐fold higher binding selectivity for α1‐adrenoceptor subtypes against β‐adrenoceptor subtypes, making it difficult for use in a β‐adrenoceptor receptor study. Compounds SWR‐0315NA and SWR‐0342SA have similar binding potency for α1‐adrenoceptors as adrenaline (epinephrine), proving the finding of this manuscript that this phenoxypropanolamine group of β‐adrenoceptor ligands could also be used as α1‐adrenoceptor ligands. Functional assays have to be performed to confirm their agonistic activity.