                         SEQUENCE LISTING

<110>  Hadasit Medical Research Services and Development Ltd
 
<120>  COMBINATION OF -OPIOID RECEPTOR (MOR) MODULATORS IN COMPOSITIONS
        AND METHODS FOR PREVENTING AND TREATING PAIN, SUICIDALITY AND 
       MENTAL DISORDERS

<130>  2677400

<150>  US 62/752,036
<151>  2018-10-29

<150>  US 62/811,560
<151>  2019-02-28

<160>  5     

<170>  PatentIn version 3.5

<210>  1
<211>  400
<212>  PRT
<213>  Homo sapiens


<220>
<221>  MISC_FEATURE
<223>  Homo sapiens MOR-1 as denoted by NCBI Reference Sequence: 
       NP_000905.3

<400>  1

Met Asp Ser Ser Ala Ala Pro Thr Asn Ala Ser Asn Cys Thr Asp Ala 
1               5                   10                  15      


Leu Ala Tyr Ser Ser Cys Ser Pro Ala Pro Ser Pro Gly Ser Trp Val 
            20                  25                  30          


Asn Leu Ser His Leu Asp Gly Asn Leu Ser Asp Pro Cys Gly Pro Asn 
        35                  40                  45              


Arg Thr Asp Leu Gly Gly Arg Asp Ser Leu Cys Pro Pro Thr Gly Ser 
    50                  55                  60                  


Pro Ser Met Ile Thr Ala Ile Thr Ile Met Ala Leu Tyr Ser Ile Val 
65                  70                  75                  80  


Cys Val Val Gly Leu Phe Gly Asn Phe Leu Val Met Tyr Val Ile Val 
                85                  90                  95      


Arg Tyr Thr Lys Met Lys Thr Ala Thr Asn Ile Tyr Ile Phe Asn Leu 
            100                 105                 110         


Ala Leu Ala Asp Ala Leu Ala Thr Ser Thr Leu Pro Phe Gln Ser Val 
        115                 120                 125             


Asn Tyr Leu Met Gly Thr Trp Pro Phe Gly Thr Ile Leu Cys Lys Ile 
    130                 135                 140                 


Val Ile Ser Ile Asp Tyr Tyr Asn Met Phe Thr Ser Ile Phe Thr Leu 
145                 150                 155                 160 


Cys Thr Met Ser Val Asp Arg Tyr Ile Ala Val Cys His Pro Val Lys 
                165                 170                 175     


Ala Leu Asp Phe Arg Thr Pro Arg Asn Ala Lys Ile Ile Asn Val Cys 
            180                 185                 190         


Asn Trp Ile Leu Ser Ser Ala Ile Gly Leu Pro Val Met Phe Met Ala 
        195                 200                 205             


Thr Thr Lys Tyr Arg Gln Gly Ser Ile Asp Cys Thr Leu Thr Phe Ser 
    210                 215                 220                 


His Pro Thr Trp Tyr Trp Glu Asn Leu Leu Lys Ile Cys Val Phe Ile 
225                 230                 235                 240 


Phe Ala Phe Ile Met Pro Val Leu Ile Ile Thr Val Cys Tyr Gly Leu 
                245                 250                 255     


Met Ile Leu Arg Leu Lys Ser Val Arg Met Leu Ser Gly Ser Lys Glu 
            260                 265                 270         


Lys Asp Arg Asn Leu Arg Arg Ile Thr Arg Met Val Leu Val Val Val 
        275                 280                 285             


Ala Val Phe Ile Val Cys Trp Thr Pro Ile His Ile Tyr Val Ile Ile 
    290                 295                 300                 


Lys Ala Leu Val Thr Ile Pro Glu Thr Thr Phe Gln Thr Val Ser Trp 
305                 310                 315                 320 


His Phe Cys Ile Ala Leu Gly Tyr Thr Asn Ser Cys Leu Asn Pro Val 
                325                 330                 335     


Leu Tyr Ala Phe Leu Asp Glu Asn Phe Lys Arg Cys Phe Arg Glu Phe 
            340                 345                 350         


Cys Ile Pro Thr Ser Ser Asn Ile Glu Gln Gln Asn Ser Thr Arg Ile 
        355                 360                 365             


Arg Gln Asn Thr Arg Asp His Pro Ser Thr Ala Asn Thr Val Asp Arg 
    370                 375                 380                 


Thr Asn His Gln Leu Glu Asn Leu Glu Ala Glu Thr Ala Pro Leu Pro 
385                 390                 395                 400 


<210>  2
<211>  418
<212>  PRT
<213>  Homo sapiens


<220>
<221>  MISC_FEATURE
<223>  mu-type opioid receptor isoform MOR-1O NCBI Reference Sequence: 
       NP_001008503.2

<400>  2

Met Asp Ser Ser Ala Ala Pro Thr Asn Ala Ser Asn Cys Thr Asp Ala 
1               5                   10                  15      


Leu Ala Tyr Ser Ser Cys Ser Pro Ala Pro Ser Pro Gly Ser Trp Val 
            20                  25                  30          


Asn Leu Ser His Leu Asp Gly Asn Leu Ser Asp Pro Cys Gly Pro Asn 
        35                  40                  45              


Arg Thr Asp Leu Gly Gly Arg Asp Ser Leu Cys Pro Pro Thr Gly Ser 
    50                  55                  60                  


Pro Ser Met Ile Thr Ala Ile Thr Ile Met Ala Leu Tyr Ser Ile Val 
65                  70                  75                  80  


Cys Val Val Gly Leu Phe Gly Asn Phe Leu Val Met Tyr Val Ile Val 
                85                  90                  95      


Arg Tyr Thr Lys Met Lys Thr Ala Thr Asn Ile Tyr Ile Phe Asn Leu 
            100                 105                 110         


Ala Leu Ala Asp Ala Leu Ala Thr Ser Thr Leu Pro Phe Gln Ser Val 
        115                 120                 125             


Asn Tyr Leu Met Gly Thr Trp Pro Phe Gly Thr Ile Leu Cys Lys Ile 
    130                 135                 140                 


Val Ile Ser Ile Asp Tyr Tyr Asn Met Phe Thr Ser Ile Phe Thr Leu 
145                 150                 155                 160 


Cys Thr Met Ser Val Asp Arg Tyr Ile Ala Val Cys His Pro Val Lys 
                165                 170                 175     


Ala Leu Asp Phe Arg Thr Pro Arg Asn Ala Lys Ile Ile Asn Val Cys 
            180                 185                 190         


Asn Trp Ile Leu Ser Ser Ala Ile Gly Leu Pro Val Met Phe Met Ala 
        195                 200                 205             


Thr Thr Lys Tyr Arg Gln Gly Ser Ile Asp Cys Thr Leu Thr Phe Ser 
    210                 215                 220                 


His Pro Thr Trp Tyr Trp Glu Asn Leu Leu Lys Ile Cys Val Phe Ile 
225                 230                 235                 240 


Phe Ala Phe Ile Met Pro Val Leu Ile Ile Thr Val Cys Tyr Gly Leu 
                245                 250                 255     


Met Ile Leu Arg Leu Lys Ser Val Arg Met Leu Ser Gly Ser Lys Glu 
            260                 265                 270         


Lys Asp Arg Asn Leu Arg Arg Ile Thr Arg Met Val Leu Val Val Val 
        275                 280                 285             


Ala Val Phe Ile Val Cys Trp Thr Pro Ile His Ile Tyr Val Ile Ile 
    290                 295                 300                 


Lys Ala Leu Val Thr Ile Pro Glu Thr Thr Phe Gln Thr Val Ser Trp 
305                 310                 315                 320 


His Phe Cys Ile Ala Leu Gly Tyr Thr Asn Ser Cys Leu Asn Pro Val 
                325                 330                 335     


Leu Tyr Ala Phe Leu Asp Glu Asn Phe Lys Arg Cys Phe Arg Glu Phe 
            340                 345                 350         


Cys Ile Pro Thr Ser Ser Asn Ile Glu Gln Gln Asn Ser Thr Arg Ile 
        355                 360                 365             


Arg Gln Asn Thr Arg Asp His Pro Ser Thr Ala Asn Thr Val Asp Arg 
    370                 375                 380                 


Thr Asn His Gln Pro Pro Leu Ala Val Ser Met Ala Gln Ile Phe Thr 
385                 390                 395                 400 


Arg Tyr Pro Pro Pro Thr His Arg Glu Lys Thr Cys Asn Asp Tyr Met 
                405                 410                 415     


Lys Arg 
        


<210>  3
<211>  392
<212>  PRT
<213>  Homo sapiens


<220>
<221>  MISC_FEATURE
<223>  mu-type opioid receptor isoform MOR-1A NCBI Reference Sequence: 
       NP_001008504.2

<400>  3

Met Asp Ser Ser Ala Ala Pro Thr Asn Ala Ser Asn Cys Thr Asp Ala 
1               5                   10                  15      


Leu Ala Tyr Ser Ser Cys Ser Pro Ala Pro Ser Pro Gly Ser Trp Val 
            20                  25                  30          


Asn Leu Ser His Leu Asp Gly Asn Leu Ser Asp Pro Cys Gly Pro Asn 
        35                  40                  45              


Arg Thr Asp Leu Gly Gly Arg Asp Ser Leu Cys Pro Pro Thr Gly Ser 
    50                  55                  60                  


Pro Ser Met Ile Thr Ala Ile Thr Ile Met Ala Leu Tyr Ser Ile Val 
65                  70                  75                  80  


Cys Val Val Gly Leu Phe Gly Asn Phe Leu Val Met Tyr Val Ile Val 
                85                  90                  95      


Arg Tyr Thr Lys Met Lys Thr Ala Thr Asn Ile Tyr Ile Phe Asn Leu 
            100                 105                 110         


Ala Leu Ala Asp Ala Leu Ala Thr Ser Thr Leu Pro Phe Gln Ser Val 
        115                 120                 125             


Asn Tyr Leu Met Gly Thr Trp Pro Phe Gly Thr Ile Leu Cys Lys Ile 
    130                 135                 140                 


Val Ile Ser Ile Asp Tyr Tyr Asn Met Phe Thr Ser Ile Phe Thr Leu 
145                 150                 155                 160 


Cys Thr Met Ser Val Asp Arg Tyr Ile Ala Val Cys His Pro Val Lys 
                165                 170                 175     


Ala Leu Asp Phe Arg Thr Pro Arg Asn Ala Lys Ile Ile Asn Val Cys 
            180                 185                 190         


Asn Trp Ile Leu Ser Ser Ala Ile Gly Leu Pro Val Met Phe Met Ala 
        195                 200                 205             


Thr Thr Lys Tyr Arg Gln Gly Ser Ile Asp Cys Thr Leu Thr Phe Ser 
    210                 215                 220                 


His Pro Thr Trp Tyr Trp Glu Asn Leu Leu Lys Ile Cys Val Phe Ile 
225                 230                 235                 240 


Phe Ala Phe Ile Met Pro Val Leu Ile Ile Thr Val Cys Tyr Gly Leu 
                245                 250                 255     


Met Ile Leu Arg Leu Lys Ser Val Arg Met Leu Ser Gly Ser Lys Glu 
            260                 265                 270         


Lys Asp Arg Asn Leu Arg Arg Ile Thr Arg Met Val Leu Val Val Val 
        275                 280                 285             


Ala Val Phe Ile Val Cys Trp Thr Pro Ile His Ile Tyr Val Ile Ile 
    290                 295                 300                 


Lys Ala Leu Val Thr Ile Pro Glu Thr Thr Phe Gln Thr Val Ser Trp 
305                 310                 315                 320 


His Phe Cys Ile Ala Leu Gly Tyr Thr Asn Ser Cys Leu Asn Pro Val 
                325                 330                 335     


Leu Tyr Ala Phe Leu Asp Glu Asn Phe Lys Arg Cys Phe Arg Glu Phe 
            340                 345                 350         


Cys Ile Pro Thr Ser Ser Asn Ile Glu Gln Gln Asn Ser Thr Arg Ile 
        355                 360                 365             


Arg Gln Asn Thr Arg Asp His Pro Ser Thr Ala Asn Thr Val Asp Arg 
    370                 375                 380                 


Thr Asn His Gln Val Arg Ser Leu 
385                 390         


<210>  4
<211>  446
<212>  PRT
<213>  Homo sapiens


<220>
<221>  MISC_FEATURE
<223>  mu-type opioid receptor isoform MOR-1X NCBI Reference Sequence: 
       NP_001008505.2

<400>  4

Met Asp Ser Ser Ala Ala Pro Thr Asn Ala Ser Asn Cys Thr Asp Ala 
1               5                   10                  15      


Leu Ala Tyr Ser Ser Cys Ser Pro Ala Pro Ser Pro Gly Ser Trp Val 
            20                  25                  30          


Asn Leu Ser His Leu Asp Gly Asn Leu Ser Asp Pro Cys Gly Pro Asn 
        35                  40                  45              


Arg Thr Asp Leu Gly Gly Arg Asp Ser Leu Cys Pro Pro Thr Gly Ser 
    50                  55                  60                  


Pro Ser Met Ile Thr Ala Ile Thr Ile Met Ala Leu Tyr Ser Ile Val 
65                  70                  75                  80  


Cys Val Val Gly Leu Phe Gly Asn Phe Leu Val Met Tyr Val Ile Val 
                85                  90                  95      


Arg Tyr Thr Lys Met Lys Thr Ala Thr Asn Ile Tyr Ile Phe Asn Leu 
            100                 105                 110         


Ala Leu Ala Asp Ala Leu Ala Thr Ser Thr Leu Pro Phe Gln Ser Val 
        115                 120                 125             


Asn Tyr Leu Met Gly Thr Trp Pro Phe Gly Thr Ile Leu Cys Lys Ile 
    130                 135                 140                 


Val Ile Ser Ile Asp Tyr Tyr Asn Met Phe Thr Ser Ile Phe Thr Leu 
145                 150                 155                 160 


Cys Thr Met Ser Val Asp Arg Tyr Ile Ala Val Cys His Pro Val Lys 
                165                 170                 175     


Ala Leu Asp Phe Arg Thr Pro Arg Asn Ala Lys Ile Ile Asn Val Cys 
            180                 185                 190         


Asn Trp Ile Leu Ser Ser Ala Ile Gly Leu Pro Val Met Phe Met Ala 
        195                 200                 205             


Thr Thr Lys Tyr Arg Gln Gly Ser Ile Asp Cys Thr Leu Thr Phe Ser 
    210                 215                 220                 


His Pro Thr Trp Tyr Trp Glu Asn Leu Leu Lys Ile Cys Val Phe Ile 
225                 230                 235                 240 


Phe Ala Phe Ile Met Pro Val Leu Ile Ile Thr Val Cys Tyr Gly Leu 
                245                 250                 255     


Met Ile Leu Arg Leu Lys Ser Val Arg Met Leu Ser Gly Ser Lys Glu 
            260                 265                 270         


Lys Asp Arg Asn Leu Arg Arg Ile Thr Arg Met Val Leu Val Val Val 
        275                 280                 285             


Ala Val Phe Ile Val Cys Trp Thr Pro Ile His Ile Tyr Val Ile Ile 
    290                 295                 300                 


Lys Ala Leu Val Thr Ile Pro Glu Thr Thr Phe Gln Thr Val Ser Trp 
305                 310                 315                 320 


His Phe Cys Ile Ala Leu Gly Tyr Thr Asn Ser Cys Leu Asn Pro Val 
                325                 330                 335     


Leu Tyr Ala Phe Leu Asp Glu Asn Phe Lys Arg Cys Phe Arg Glu Phe 
            340                 345                 350         


Cys Ile Pro Thr Ser Ser Asn Ile Glu Gln Gln Asn Ser Thr Arg Ile 
        355                 360                 365             


Arg Gln Asn Thr Arg Asp His Pro Ser Thr Ala Asn Thr Val Asp Arg 
    370                 375                 380                 


Thr Asn His Gln Cys Leu Pro Ile Pro Ser Leu Ser Cys Trp Ala Leu 
385                 390                 395                 400 


Glu Gln Gly Cys Leu Val Val Tyr Pro Gly Pro Leu Gln Gly Pro Leu 
                405                 410                 415     


Val Arg Tyr Asp Leu Pro Ala Ile Leu His Ser Ser Cys Leu Arg Gly 
            420                 425                 430         


Asn Thr Ala Pro Ser Pro Ser Gly Gly Ala Phe Leu Leu Ser 
        435                 440                 445     


<210>  5
<211>  493
<212>  PRT
<213>  Homo sapiens


<220>
<221>  MISC_FEATURE
<223>  mu-type opioid receptor isoform MOR-1i  NCBI Reference Sequence: 
       NP_001138751.1

<400>  5

Met Cys Leu His Arg Arg Val Pro Ser Glu Glu Thr Tyr Ser Leu Asp 
1               5                   10                  15      


Arg Phe Ala Gln Asn Pro Pro Leu Phe Pro Pro Pro Ser Leu Pro Ala 
            20                  25                  30          


Ser Glu Ser Arg Met Ala His Ala Pro Leu Leu Gln Arg Cys Gly Ala 
        35                  40                  45              


Ala Arg Thr Gly Phe Cys Lys Lys Gln Gln Glu Leu Trp Gln Arg Arg 
    50                  55                  60                  


Lys Glu Ala Ala Glu Ala Leu Gly Thr Arg Lys Val Ser Val Leu Leu 
65                  70                  75                  80  


Ala Thr Ser His Ser Gly Ala Arg Pro Ala Val Ser Thr Met Asp Ser 
                85                  90                  95      


Ser Ala Ala Pro Thr Asn Ala Ser Asn Cys Thr Asp Ala Leu Ala Tyr 
            100                 105                 110         


Ser Ser Cys Ser Pro Ala Pro Ser Pro Gly Ser Trp Val Asn Leu Ser 
        115                 120                 125             


His Leu Asp Gly Asn Leu Ser Asp Pro Cys Gly Pro Asn Arg Thr Asp 
    130                 135                 140                 


Leu Gly Gly Arg Asp Ser Leu Cys Pro Pro Thr Gly Ser Pro Ser Met 
145                 150                 155                 160 


Ile Thr Ala Ile Thr Ile Met Ala Leu Tyr Ser Ile Val Cys Val Val 
                165                 170                 175     


Gly Leu Phe Gly Asn Phe Leu Val Met Tyr Val Ile Val Arg Tyr Thr 
            180                 185                 190         


Lys Met Lys Thr Ala Thr Asn Ile Tyr Ile Phe Asn Leu Ala Leu Ala 
        195                 200                 205             


Asp Ala Leu Ala Thr Ser Thr Leu Pro Phe Gln Ser Val Asn Tyr Leu 
    210                 215                 220                 


Met Gly Thr Trp Pro Phe Gly Thr Ile Leu Cys Lys Ile Val Ile Ser 
225                 230                 235                 240 


Ile Asp Tyr Tyr Asn Met Phe Thr Ser Ile Phe Thr Leu Cys Thr Met 
                245                 250                 255     


Ser Val Asp Arg Tyr Ile Ala Val Cys His Pro Val Lys Ala Leu Asp 
            260                 265                 270         


Phe Arg Thr Pro Arg Asn Ala Lys Ile Ile Asn Val Cys Asn Trp Ile 
        275                 280                 285             


Leu Ser Ser Ala Ile Gly Leu Pro Val Met Phe Met Ala Thr Thr Lys 
    290                 295                 300                 


Tyr Arg Gln Gly Ser Ile Asp Cys Thr Leu Thr Phe Ser His Pro Thr 
305                 310                 315                 320 


Trp Tyr Trp Glu Asn Leu Leu Lys Ile Cys Val Phe Ile Phe Ala Phe 
                325                 330                 335     


Ile Met Pro Val Leu Ile Ile Thr Val Cys Tyr Gly Leu Met Ile Leu 
            340                 345                 350         


Arg Leu Lys Ser Val Arg Met Leu Ser Gly Ser Lys Glu Lys Asp Arg 
        355                 360                 365             


Asn Leu Arg Arg Ile Thr Arg Met Val Leu Val Val Val Ala Val Phe 
    370                 375                 380                 


Ile Val Cys Trp Thr Pro Ile His Ile Tyr Val Ile Ile Lys Ala Leu 
385                 390                 395                 400 


Val Thr Ile Pro Glu Thr Thr Phe Gln Thr Val Ser Trp His Phe Cys 
                405                 410                 415     


Ile Ala Leu Gly Tyr Thr Asn Ser Cys Leu Asn Pro Val Leu Tyr Ala 
            420                 425                 430         


Phe Leu Asp Glu Asn Phe Lys Arg Cys Phe Arg Glu Phe Cys Ile Pro 
        435                 440                 445             


Thr Ser Ser Asn Ile Glu Gln Gln Asn Ser Thr Arg Ile Arg Gln Asn 
    450                 455                 460                 


Thr Arg Asp His Pro Ser Thr Ala Asn Thr Val Asp Arg Thr Asn His 
465                 470                 475                 480 


Gln Leu Glu Asn Leu Glu Ala Glu Thr Ala Pro Leu Pro 
                485                 490             


